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[PharmApp] - Các phần mềm và nền tảng dùng trong nghiên cứu phát triển công thức thuốc và nghiên cứu lâm sàng

12/08/2022

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Fig. 1.3 The funnel of drug discovery. Copyright with Springer Nature. Reproduced from [166]

Some significant developments of 1960s

Interesting development	Application	Developer/team/ organization	Year	Ref.
FORTRAN IV	First programming language mainly used for numeric and scientific computations	IBM	1962 (FORTRAN IV)	[12]
Simula	Simulation  programming language	Kristen Nygaard at Norwegian Computing Center, Oslo	1962	[18]
SNOBOL	Programming language—string- oriented and symbolic language	David J. Farber, Ralph E. Griswold, and Ivan P. Polonsky, AT&T Bell Laboratories	1962	[19]
Quantum Chemistry Program Exchange (QCPE)	Repository of programs and softwares for sharing codes	Prof. Shull and colleagues from Air Force Office of Aerospace Research (ARAC), Indiana University	1963	[21]
FORMAC	The first computer algebra system	Jean E. Simmet from IBM	1964	[17]
QSAR Modelling	Method for determination of biological activity by correlating it with chemical structure of compound	Corwin Hansch and Toshio Fujita	1964	[24]
Mathematical equations	Developed methods to mathematically report the toxicity profile of chemicals	Spencer M. Free and James W. Wilson	1964	[25]
BMDP	Software used for Statistical data analysis	Wilfrid Dixon from University of California	1965	[26]
SAMCEF	Software used for finite- element analysis	SAMTECH	1965	[27]
ORTEP	Software used for crystal structure illustrations	Oak Ridge National Laboratory (ORNL)	1965	[28]
CSMP III	Software used for Solving and modeling of differential  equations	IBM	1967	[29]
SPSS	Software used for statistical data analysis	University of Stanford (Norman H. Nie, C. Hadlai (Tex) Hull, and Dale H. Bent)	1968	[20]
Mouse	For pointing and for improving speed and accuracy of computers	Douglas Engelbart	1968	[14]
RKS 100-86 (Rollkugel- Steuerung)	First rolling ball mouse	Rainer Mallebrein of Telefunken, Germany	1968	[16]

Some significant developments of 1970s

Interesting development	Application	Developer/team/ organization	Year	Ref.
Gaussian	Software used for computational  chemistry	Prof. John A Pople’s from Carnegie Mellon University	1970	[35]
ARPANET’s Netword e-mail System; First electronic mail program	Wide-area packet- switching network	Ray Tomilson at Advanced Research Projects Agency (ARPA)	1971	[52]
Protein Data Bank (PDB)	Database of protein structures	Walter Hamilton at Brookhaven National Laboratory	1971	[39]
UNIX	Computer operating system	Ken Thompson, Dennis Ritchie, Brian Kernighan, Douglas McIlroy, and Joe Ossanna at Bell Labs	1971	[53]
Floppy disk	Used for data storage	IBM	1972	[31]
SQL	Structured Query Language used in data analysis	IBM	1972	[54]
Minitab	Statistical software	Minitab LLC	1972	[42]
XTL	Software used for crystallographic study	Syntex	1974	[45]
Version 6 Unix	First version of Unix operating system	AT&T Bell Laboratories	1975	[55]
CLU	Programming language	Massachusetts  Institute of Technology	1975	[56]
BS2000	Mainframe computer operating system	Siemens AG and later by Fujitsu Technology Solutions	1975	[30, 57]
MAtrix LABoratory (MALTAB)	Educational Software package for calculations related to matrices	Cleve Moler	1976	[33]
MMI/MMPI	Software launched on QCEP platform for making chemical structures with increased accuracy	N L Allinger from University of Georgia	1976	[21]
SAS	Software for statistical data analysis	North Carolina State University and SAS Institute	1976	[33]
VAX11/780	Minicomputer with low cost and extendable storage	Digital Equipment Corporation (DEC)	1977	[12]
Apple II	Personal computers with floppy drive so that the user can store softwares	Developed by Apple Inc.	1977	[58]

Interesting development	Application	Developer/team/ organization	Year	Ref.
General Atomic and Molecular Electronic Structure System (GAMESS)	Software for computational  chemistry	Iowa state University	1977	[43]
Quantitative Drug Design: A Critical Introduction	A book on drug design	Yvonne Connolly Martin	1978	[49]
GROningen MOlecular Simulation (GROMOS)	Software used for field force for molecular dynamics simulation	University of Groningen	1978	[44]
Word star	Word processing application for microcomputers	Rob Barnaby	1978	[59]
VisiCalc	Software used as data entry	Bob Frankston	1979	[60]

PharmApp for  developments of 1980s

Interesting development	Application	Developer/team/ organization	Year	Ref.
SYBYL	Software for molecular modeling, homolog recognition, structure, and function prediction	Tripos (now Certara from 2008)	Early 1980s	[87, 88]
Super Calc	Software used as advanced calculator app, which is used available on smartphones and tablets	Sorcim	1980	[83]
VAX-11/780;	Minicomputers, 8000	Digital Equipment	1977–	[6, 89,
VAX 8000 series	series, offered higher	Corporation	1989	90]
	performance than that of
	VAX-11/780
MATLAB	Software used for matrix manipulations and plotting of functions and data and implementation of algorithms	MathWorks	1980	[65]
IBM PC	Personal computer with multiuser support and multiwindow  processing	Philip Donald Estridge at IBM	1981	[91]
Xerox 8010 star system	Personal computer	Xerox Corporation	1981	[82]
Assisted Model	Software to apply force	Peter Kollman and his	1981	[71, 92,
Building with	fields for molecular	team at University of		93]
Energy	dynamics of	California
Refinement	biomolecules
(AMBER)
CLOGP	Software used for predicting lipophilicity	Prof. Al Leo at Pomona College	1982	[74]
Chemistry at Harvard Macromolecular Mechanics (CHARMM)	Software for molecular mechanics and molecular dynamics simulation program	Prof. Martin Karplus at Harvard University	1983	[94]
Macro Model	Program for molecular modeling of organic compounds and biopolymers; force fields plus energy minimizing algorithms	Fariborz Mohamadi and colleagues, Columbia University, New York; Schrödinger, LLC (2000 Onwards)	1986	[78, 95]
Stata	Statistical program	StataCorp	1985	[79]
Microsoft Paint	Microsoft paint is a software used as painting and graphics editing	Microsoft	1985	[96]

Interesting development	Application	Developer/team/ organization	Year	Ref.
ChemDraw	Software for chemical structure drawing, representation, NMR, and mass spectrum simulation	David A. Evans and Stewart Rubenstein, and later by CambridgeSoft, and recently by PerkinElmer from 2011	1985	[67, 68]
X-PLOR	X-PLOR is a software used for protein crystallography	Dr. Axel T. Brunger	1987	[97]
TOPKAT	Correlative SAR system	Kurt Enslein, from	Late	[75–77,
	for predicting preclinical	Health Designs	1980s	98]
	toxicity	(Accelry), and later
		acquired by Biovia
Design-Expert	Software used in statistical data analysis and design of experiments	Stat-Ease, Inc.	1988	[80]
AutoDock	Molecular modeling software	Scripps Research	1989	[73]
Python	Programming language	Guido van Rossum	1989	[99]

PharmApp for  developments of 1990s

 

Interesting development	Application	Developer/team/ organization	Year	Ref.
Linux	Operating system	Linus Torvalds at the Helsinki University of Technology, Finland; Free Software Foundation (FSF)	1990s	[100]
Integrated Scientific Information System/Draw (ISIS/Draw)	Software for 2D drawing of structures and equations; reaction validation features and could calculate formula and molecular weight	Molecular Design Limited (MDL)	1991	[106]
Windows NT	Processor-independent, multiprocessing, and multiuser operating system	Microsoft	1993	[62]
JAVA	Platform-independent programming language	James Gosling, Patrick Naughton, Chris Warth, Ed Frank, and Mike Sheridan at Sun Microsystems	1995	[102]
R	Programming language used for statistical computing and data analysis	Robert Gentleman and Ross Ihaka	1995	[103]
GastroPlus®	First commercial PBPK modeling based on advanced  compartmental absorption and transit (ACAT) model	Simulations Plus	1998	[107]

PharmApp for  developments of 2000s

 

Interesting development	Application	Developer/team/ organization	Year	Ref.
Materials Studio	Module-based molecular simulating software	Accelrys (now Biovia)	2000	[127] [62]
Discovery Studio	Module-based comprehensive  software suite for drug discovery	Accelrys (now Biovia)	2002	[128]
MOE	Integrated platform for computer-aided molecular design and drug discovery	Chemical Computing Group	Around 2000	[138]
BioSuite	Modular software for genome/proteome sequencing, 3D modeling, molecular dynamics simulation, and drug design	CSIR and TCS	2004	[139]
Glide	Virtual screening and molecular docking	Schrödinger, Inc.	2004	[129, 130, 140]
PubChem	Freely accessible database of chemical molecules and their biological activity	National Center for Biotechnology Information	2004	[132]
ZINC	Freely accessible database of biologically relevant and 3D form of the molecule for virtual screening and docking	Irwin and Shoichet Labs, University of California	2004	[141]
Surflex- Dock	Virtual screening software and docking	Tripos Inc. (Now Certara)	2006	[142]
DrugBank	Freely accessible database of drugs, drug targets, and drug actions	Dr. David Wishart, University of Alberta, and The Metabolomics Innovation Centre, University of Alberta	2006	[143]
Lead Finder	Molecular docking	Mol Tech Ltd.	2007	[144]
ChemSpider	Database	Royal Society of Chemistry	2007	[132]
DOCK Blaster	Connects ZINC databases with DOCK to ascertain suitable ligand for protein	University of California	2009	[145]

 

 Softwares for design of experiments (DOE)

 

Software, latest version, and its release date	Brief description	URL
Design-Expert Version 13, January 2021	First launch in 1988; provides 3D plots that can be rotated to visualize response surfaces; numerical and graphical optimization; and access by subscription	http://www.statease.com/
JMP Version 16; March 2021	JMP (John’s Macintosh Project) was developed in 1989; Features: control charts, elementary design of experiments (DOE), survival features, graph builder, dynamic bubble plots, data mining, predictive analytics, and automated model building; orthogonal supersaturated design; and access by subscription	https://www.jmp.com/
Minitab 20.2.0; April 2021	First launch in 1972; powerful DOE software used for automated data analysis, graphic, and help features, including MS-Excel compatibility and almost all designs of RSM; and access by subscription	https://www.minitab.com/
XLSTAT version 2021.2; April 2021	First launch in 1993; flexible Excel data analysis add-on software; helps in selection of an experimental design; DOE for screening, response surface, and mixture designs and their analysis; and access by subscription	https://www.xlstat.com/en/
Statistica 14.0; December 2020	First launch in Mid-1980s; Statistica provides data analysis, data management, statistics, data mining, machine learning, text analytics, and data visualization procedures; access by subscription	https://docs.tibco.com/products/ tibco-statistica-14-0-0
SPSS Statistics 27; November 2020	Comprehensive statistical software with features implementing experimental design	https://www.ibm.com/in-en/ products/spss-statistics
MODDE®  12; February 2017	Use for evaluation of fitting of model and suitable for response surface modeling; access by subscription	https://www.sartorius.com/en/ products/process-analytical- technology/data-analytics- software/support/knowledge-base/ modde-12-550758
Prism 9.1.0 (Graph Pad Software); March 2021	First launch in 1989; used for data analysis, statistics, and graphing	https://www.graphpad.com/

Software, latest version, and its release date	Brief description	URL
Statgraphics Centurion 19; 2020	First launch in 1980; Statgraphics provide extensive catalog of screening, response surface, optimal designs, mixture, and RPD experiments; access by subscription	http://statgraphics.com/

Types of computer systems and their application in pharmaceutical sciences

 

Advanced computing techniques in pharmaceutical  formulations	Application	Ref.
Expert- and knowledge-based systems	Generation of initial formulations and processing conditions ab initio	[31]
Neural computing	For modeling formulation and process data to explore relationships within the dataset and optimize the formulation	[5]
Computer simulation	For the development of mathematical models for the interactions between the ingredients of formulation and the manufacturing process to predict outcomes	[32]

Various pharmacokinetic softwares, their features, latest version, and platform to use

Software; latest version; release date	Brief description	Date of release of first version	URL
Phoenix; WinNonlin 8.3; June 2020	Noncompartmental  analysis (NCA), PK/PD modeling, and toxicokinetic (TK) modeling; runs on Windows	1990	https://www.certara.com/
GastroPlus® 9.8; Oct. 2020	Available as ten different modules, viz. Drug Drug Interaction, PBPKPlus™, ADMET Predictor®, Additional Dosage Routes, Metabolism and Transporter, Biologics,  Optimization, PDPlus™, PKPlus™, and IVIVCPlus™; PBPK modeling, PBBM modeling, in silico PK prediction, IVIVC prediction, virtual trials, prediction of drug-drug interactions food effects and pharmacodynamics, optimization of generic formulations, and population pharmacokinetic; runs on Windows	August 1998	https://www.simulations- plus.com/
NONMEM®	Nonlinear  mixed-effect modeling software program (NONMEM®), Population PK and PK/PD modeling (PREDPP); runs on Windows or Linux; access by subscription	1989	https://www.iconplc.com/ innovation/nonmem/
MATLAB Simbiology	PBPK, PKPD, quantitative systems pharmacology, model building either MATLAB programming or Simbiology block diagram editor;  noncompartment analysis	Late 1970 (MATLB)	https://www.mathworks. com/
Simcyp™ PBPK Simulator version 20	Physiologically based pharmacokinetic  (PBPK) modeling and simulation; models for maternal health, biowaivers, and long-acting injectable drugs; separate modules for animals, pediatric, cardiac safety, long acting, injectables, and	1999	https://www.certara.com/

Software; latest version; release date	Brief description	Date of release of first version	URL
	lactation; SimCyp founded in 1999
PK-Sim™ (Part of OSP Suite. Version 9.1; July 2020)	PK-Sim™ allows PBPK modeling and PBPK/PD modeling; based on compartmental gastrointestinal (GI) transit model; communication and exchange of data via Matlab®, R, and MS Excel; an open access suite; both PK-Sim™ and modeling software tool MoBi® are integrated into OSP; run on Windows	Mid- 1990s	http://www.open-systems- pharmacology.org/
PKBugs version 2; WinBUGS 1.4; 2007	Complex population PK/PD modeling; Markov Chain Monte Carlo methods to be applied to PK/PD analysis; no limitation of dimensional array and size; free to download; run on Windows	1997	https://www.mrc-bsu.cam.ac. uk/software/bugs/the-bugs- project-winbugs/winbugs- development/
MEDICI-PK™	Whole-body PK modeling;	Mid-	https://www.cit-wulkow.de/
	virtual PK laboratory based	2000s	products/medici-pk
	on modules; in silico	(2005–
	comparative PK studies of	2006)
	different species, different
	individuals,  different
	compounds, and/or different
	models; bidirectional
	interface to Microsoft Excel;
	access by subscription
Kinetica 5.1 2014	Noncompartment, compartment, and population PK/PD modeling; bioequivalence, protein, and enzyme kinetics computations; data communication with Thermo Scientific Watson LIMS™, MS Excel, Oracle, and others; access by subscription		https://www.thermofisher. com/

 

Software used in Quality by Design (QbD)

 

Sr. no.	Software	Features
1.	Fusion QbD	Advanced approach toward experimental design and multivariate analysis
2.	Master control QbD	Effective and efficient implementation of principles of QbD
3.	Lean QbD	Knowledge-assisted structured applications that can perform several tasks related to QbD implementation
4.	QbD Vision
5.	QbD Software

List of software used for 3D printing

 

Software	Function	Level	System requirement
3D Builder	Design	Beginner	Windows
3D Slash	Design	Beginner	Browser
3DPrinterOS	STL Editor	Beginner	Windows, Mac, Ubuntu, Raspberry Pi
3D-Tool Free Viewer	STL Analysis	Intermediate	Windows
AstroPrint	Slicer, 3D Printer Host	Beginner	Browser
Blender	Design	Professional	Windows, Mac, Linux
FreeCAD	Design	Intermediate	Windows, Mac, Linux
Fusion 360	Design	Intermediate	Windows, Mac
KISSlicer	Slicer	Intermediate	Windows, Mac, Linux
MakerBot Print	Slicer, 3D Printer Design	Beginner	Windows, Mac, Linux
MatterControl 2.0	Slicer, 3D Printer Host, Design	Beginner	Windows, Mac, Linux
MeshLab	STL Editor, STL Repair	Professional	Windows, Mac, Linux
Netfabb	STL Repair, Slicer	Professional	Windows
OctoPrint	Slicer, 3D Printer Host	Intermediate	Windows, Mac, Linux
OnShape	Design	Professional	Browser
OpenSCAD	Design	Intermediate	Windows, Mac, Linux
PrusaSlicer	Slicer	Beginner	Windows, Mac, Linux
Repetier-Host	Slicer, 3D Printer Host	Intermediate	Windows, Mac, Linux
Rhinoceros 3D	Design	Beginner	Windows, Mac, Linux
SketchUp Free	Design	Intermediate	Browser
SliceCrafter	Slicer	Intermediate	Browser
Solidworks	Design	Beginner	Windows, Mac, Linux
TinkerCAD	Design	Beginner	Browser
Ultimaker Cura	Slicer, 3D Printer Host	Beginner	Windows, Mac, Linux
Vectary	Design	Intermediate	Browser
ZBrushCoreMini	Design	Beginner	Windows, Mac

 

 List of research findings done on the 3D printed formulations

 

3D printing technology	Formulation	Application	Materials	Ref.
3D printing based on powder layering	Absorbable device	Novel controlled releasing drug delivery system	Polycaprolactone  (PCL) with methylene blue and polyethylene oxide matrix materials	[78]
	Tablet dosage form	Novel delayed drug release formulation	Drug and fluorescein disodium salt, Eudragit, acetone, polyvinylpyrrolidone,  and other excipients	[62]
	Implants	Multi-drug implants for bone tuberculosis	Isoniazid, rifampicin, and other excipients	[79]
	Bioceramic implants	Formulation comprising antibiotics	Vancomycin hydrochloride,  tetracycline hydrochloride, and ofloxacin with other excipients	[80]
	Mesoporous biologically active glass	Biologically active glass for restoration of bone	Dexamethasone powder and polyvinyl alcohol	[81]
	Tablet dosage form	Rapid disintegrating soft tablets	Paracetamol and other excipients	[65]
	Tablet dosage form	Controlled drug delivery system	Paracetamol and other excipients	[82]
	Tablet dosage form	Featured complex drug-releasing formulation	Chlorpheniramine  maleate and other excipients	[67]
	Cubical architecture	Consistent rate drug-releasing formulation	Pseudoephedrine hydrochloride and related excipients	[83]
	Implantable formulation	Antibiotic laden implant	Antibiotic drug and excipients	[84]
	Multiple- layered drug- eluting device	A multiple-layered drug-eluting device in the form of a doughnut	Paracetamol and excipients	[85]
	Orally dispersible formulation	Quick dispersible dosage form	Levetiracetam and other excipients	[86]
	Implantable formulation	The implantable complex design meant for prophylaxis action	Antibiotic drug and excipients	[87]
	Hydraulic adhesive material	Restoration of bone structure	Tricalcium derivative cement and other excipients	[88]

3D printing technology	Formulation	Application	Materials	Ref.
		using cementing material
Selective Laser Sintering 3D printing	Shell core structure	Controlled drug- releasing device	Polyamide	[89]
	Cubical hollow matrices	Perforated matrix devices	Nylon and other dyes	[90]
	Biopolymeric microstructures	Drug-eluting polymeric discs	PLA	[91]
Fused Deposition Modelling technology	Tablet dosage form	Controlled drug delivery system as personalized medicine	PVA	[64]
	Tablet dosage form	Various geometrical- shaped printlets	Paracetamol	[92]
	Capsule	Pulsatile drug delivery system	Paracetamol and other excipients	[93]
	Tablet dosage form	Modified release drug delivery form	PVA	[94]
	Tablet dosage form	Extended drug- releasing formulation	Steroid and PVA	[95]
	Tablet dosage form	Flexi-dose formulation	Theophylline and Eudragit	[96]
	Discs	Medical devices	Nitrofurantoin and excipients	[97]
	Discs	Drug laden implants	Nitrofurantoin and excipients	[98]
	Structured matrix reservoir	Controlled releasing matrices	Dye and excipients	[99]
	Medical devices	Sustained releasing dosage form containing chemotherapeutic drugs	Chemotherapeutic  drugs and excipients	[100]
Combinational 3D printing	Implantable device	3D printed formulation	Antibiotic and excipients	[101]

List of tools and databases used in computational modeling

 

S. no.	Tools	URL address	Category
1.	PubChem	https://pubchem.ncbi.nlm.nih.gov	Ligand databases
2.	ChEMBL	https://www.ebi.ac.uk/chembl/
3.	DrugBank	https://www.drugbank.ca
4.	DrugMatrix	https://ntp.niehs.nih.gov/results/ drugmatrix/index.html
5.	Binding database	https://www.bindingdb.org/bind/index. jsp
6.	Protein information resource (PIR)	https://proteininformationresource.org/	Protein databases
7.	SWISS-PROT	https://www.uniprot.org/statistics/ Swiss-Prot
8.	TrEMBL	https://www.ebi.ac.uk/training/online/ glossary/uniprotkbtrembl
9.	GenBank	https://www.ncbi.nlm.nih.gov/genbank/
10.	RefSeq	https://www.ncbi.nlm.nih.gov/refseq/
11.	Protein Data Bank (PDB)	https://www.rcsb.org/
12.	Simcyp™	http://www.simcyp.com	PBPK model- based software
13.	GastroPlus™	http://www.simulations-plus.com
14.	PK-Sim™	http://www.pksim.com/
15.	MEDICI-PK™	http://www.cit-wulkow.de/
16.	Cloe PK™	http://www.cyprotex.com

 Isolated organ and cell simulation modeling software

 

S. no.		Isolated organ modeling softwares		Application	Reference
1.		Cellular Potts modeling and subcellular elemental model (SEM)		Analyze cell movement, cell-cell interactions, and response to an external chemotactic gradient	[108]
2.		xPULM		An electromechanical respiratory in silico, ex vivo lung simulator	[109]
3.		“Bodylight.js.Simulator”		A visual editor for creating in-browser dynamic applications and visualizations	[110]
4.		EXSIMO		An executable simulation model combines data and code with the execution environment to run the computational analysis in an automated manner using tools from software engineering	[111]
5.		DILIsym model		Quantitative systems toxicology software for modeling drug-induced injury	[112]
	Cell modeling software		Application		Reference
6.	cBioPortal		An interactive open-source platform designed for visualizing and analyzing genomics data and selecting better treatments for patients		[113]
7.	CompuCell3D		A multicell computer simulation method for finite- element mechanistic modeling, in silico study of multicell phenomena at the tissue scale based on biologically observed cell behavior and interactions such as movement, adhesion, growth, death, mitosis, secretion of chemicals, chemotaxis, etc.		[90]
8.	“MITOsym”		MITOsym includes the primary, essential biochemical pathways associated with hepatocellular respiration and bioenergetics, including mitochondrial oxidative phosphorylation, electron transport chain activity, mitochondrial membrane potential, and glycolysis		[93]
9.	MecaGen		MecaGen enables the specification and control of complex collective movements in 3D space through a biologically relevant gene regulatory network and parameter space exploration		[92]
10.	E-CELL simulation model		A simulator of cellular system		[106]

 List of computational simulation software and their applications

 

S. no.	Modeling and simulation software	Application	URL
1.	Simcyp™ Simcyp Pediatric, Simcyp Cardiac Safety Simulator (CSS), Simcyp Lactation, PBPK simulator	Simulates drug-drug interaction, absorption modeling, dosing for special populations, and PK prediction	https://www.certara. com/software/ simcyp-pbpk/
2.	GastroPlus®	Simulates intravenous, oral, oral cavity, ocular, inhalation, dermal, subcutaneous, intramuscular  absorption, biopharmaceutics, pharmacokinetics, and pharmacodynamic parameters in humans and animals	https://www. simulation-plus.com/ software/gastroplus/
3.	PKPlus™	Estimates  noncompartmental pharmacokinetic (PK) parameters, along with one-, two-, and three- compartment PK models from pharmacokinetic studies (IV and/or oral) without the need to run full simulations	https://www. simulation-plus.com/ software/gastroplus/ pk-models/
4.	DDDPlus™	Simulates in vitro dissolution for formulation and analytical of active pharmaceutical ingredients (API) and formulation excipients under various experimental conditions in seconds	https://www. simulation-plus.com/ software/dddplus/
5.	PDPlus™	To predict the PD effect due to alteration in dose, dosage form, and dosing regimens and determine the action’s kinetics. Multiple PD models (therapeutic and adverse) can be accommodated for each drug record	https://www. simulation-plus. com//software/ gastroplus/pkpd- modeling/
6.	MembranePlus™	A software that determines in vitro permeability, in vivo absorption, and systemic clearance/distribution  with the advanced compartmental absorption and transit (ACAT™) and PBPK models. It also provides in vitro permeability (human colon adenocarcinoma (Caco-2), parallel artificial membrane permeability assay	https://www. simulation-plus.com/ software/ membraneplus/

S. no.	Modeling and simulation software	Application	URL
		(PAMPA), or Madin-Derby canine kidney (MDCK)) for optimization
7.	DILIsym® and NAFLDsym®	DILIsym is quantitative systems toxicology (QST) software for potential drug- induced liver injury (DILI) responses at various development stages	https://www. simulation-plus.com/ software/dilisym/
8.	GROMACS	The most widely used open- source free software codes in chemistry, used primarily for dynamical simulations of biomolecules, proteins, lipids, and nucleic acids	https:www.gromacs. org [133]
9.	MODELLER	A program for automated protein homology modeling	https://salilab.org/ modeller/ https://www.ncbi. nlm.nih.gov/pmc/ articles/ PMC4186674/
10.	Macromoltek	A molecular simulations software for antibody modeling, side-chain packaging, renumbering, and other web-based computational tools for antibody development	https://www. macromoltek.com

Commercially available PBPK platforms along with their associated links

 

Software

Developer/distributor

Associated links

Custom physiologically based pharmacokinetics (PBPK) software

Simcyp Simulator	Simcyp Ltd	https://www.certara.com/software- old/physiologically-based- pharmacokinetic-modeling-and- simulation/simcyp-simulator/? ap¼PKPD
GastroPlus	Simulations Plus Inc.	https://www.simulations-plus.com/ software/gastroplus/
PK-Sim	Bayer Technology Services	http://www.systems-biology.com/ products/pk-sim/
Cloe Predict	Cyprotex Ltd	https://www.cyprotex.com/insilico/ physiological_modelling/cloe-pk/

General purpose high-level scientific computing software

Berkeley Madonna	University of California at Berkeley	http://www.berkeleymadonna.com/
MATLAB and Simulink product families	The MathWorks Inc.	https://in.mathworks.com/products/ matlab.html?s_tid¼hp_products_ matlab
MLAB	Civilized Software Inc.	http://www.civilized.com/mlabdesc. html
GNU Octave	GNU	https://www.gnu.org/software/ octave/
Ecolego	AFRY	https://www.ecolego.se/ecolego/
GNU MCSim	GNU	https://www.gnu.org/software/ mcsim/

Bio-mathematical modeling software

ADAPT 5	Biomedical Simulations Resource, University of Southern California	https://bmsr.usc.edu/software/adapt/
ModelMaker	ModelKinetix	https://www.apbenson.com/ modelkinetix-downloads
NONMEM	ICON	https://www.iconplc.com/ innovation/nonmem/
STELLA	Isee systems Inc.	https://www.iseesystems.com/store/ products/stella-architect.aspx
WinNonlin	Pharsight, a Certara company	https://www.certara.com/pkpd- modeling-and-simulation-2/ phoenix-winnonlin-2/?ap¼PKPD
SAAM II	The Epsilon Group	https://tegvirginia.com/software/ saam-ii/
acslX	The AEgis Technologies Group Inc.	http://www.acslx.com/products/ toolkits.shtml
PhysioLab	Entelos Inc.	http://www.entelos.com/
PKQuest	University of Minnesota	http://www.pkquest.com/
gCOAS	Process Systems Enterprise	https://www.psenterprise.com/ products/gcoas/

Software	Developer/distributor	Associated links
COPASI	Biocomplexity Institute of Virginia Tech, University of Heidelberg, University of Connecticut, UConn Health	http://copasi.org/
Maxsim2	Fraunhofer-Chalmers  Research Centre	http://www.maxsim2.com/
AIMT7: RVIS	Health and Safety Laboratory	http://cefic-lri.org/projects/aimt7- rvis-open-access-pbpk-modelling- platform/
ADME WorkBench	AEgis Technologies	http://www.admewb.com

Summary of clinical trial phases

 

Phase	Objective	Number of participants	References
Phase 0: Pre-clinical study	•      Study of safety and efficacy in laboratory animals •      Determine safety, dose range of drug in experimental laboratory animals	As per study requirement	[1, 2]
Phase I: Clinical pharmacology	•      Determine safety of drug dose in human •      Evaluate therapeutic dose range •      Identify side effects of the treatment	20–80	[1, 2]
Phase II: Drug efficacy/ safety, dose ranging	•      Determine effectiveness of the treatment •      Evaluate safety to all pharmacological parameters	100–300	[1, 2]
Phase III: Long-term, large scale, confirmatory	•      Evaluate therapeutic effectiveness •      Monitoring the side effects •      Comparison with available treatments	1000–5000	[1, 2]
Phase IV: Post-market monitoring	•      Determine adverse drug reaction after marketing of drug in wide population •      Evaluate long-term safety	1000+	[1, 2]

 Use of computer technology in clinical development stages

 

Sr. no.	Clinical development stages	Softwares	Applications	References
1	Protocol design	Verified Clinical Trials (VCT), TriNetX	Analyze protocols	[11, 12]
2	Patient management	PatientsLikeMe,  TrialSpark, TrialX, SubjectWell, StudyKIK, Seeker Health, mProve Health, Langland, Clinical Connection, Comprehend Clinically, and FindMeCure	Patient recruitment and retention	[11, 12]
3	Clinical data management	Electronic data capturing (EDC) like Oracle Clinical, Medidata Rave and Inform by Phase Forward Electronic health records (EHR)	Capture, store and manage all safety data	[11, 12]
4	Study monitoring	Oracle Clinical, Phase Forward, NetRegulus, Aris Global	Adverse event reporting	[11, 12]
5	Regulatory reporting	SyTech, Wimmer systems	Data analysis and reporting, regulatory submission	[11, 12]

 Differences among AI, ML, and DL

 

Artificial intelligence (AI)	Machine learning (ML)	Deep learning (DL)
AI originated around the 1950s	ML originated around the 1960s	DL originated around the 1970s
The study of pattern recognition and mimicking human behavior by machines can be described as AI	It is a subset of AI and can be described as the study of computer algorithms which improves automatically through experience and by use of data	It is a subset of ML and AI which is based on Artificial neural networks (ANN) to mimic human brain-like behaviors
AI focuses on learning, reasoning, and self-correction	ML focuses on learning through experience without any human intervention	ML focuses on information processing pattern mechanisms to identify patterns just like the human brain
AI exhibits intelligence through decision-making	ML is an AI algorithm which allows systems to learn from data	In the case of DL, the ANN analyzes the data and provides output
Efficiency of AI is based on the efficiency provided by the ML or DL	Less efficient as compared to DL and cannot work properly for a higher amount of data	The most efficient and powerful than ML as it can easily work through a large set of data
Three broad categories of AI are ANI, AGI, and ASI	Four broad categories are supervised,  unsupervised, semi-supervised, and reinforcement learning	Some deep neural networks are convolutional, recurrent, autoencoder, generative adversarial network, etc.

 

Some AI tools used in drug discovery

 

AI tool	AI approach	Application	Ref
Hit Dexter	Randomized trees classifiers (ML approach)	Prediction of small molecule for positive response in biochemical assays. Available at https:// nerdd.univie.ac.at/ hitdexter/	[103, 104]
HitPick	B-score method (hit identification) and combination of Laplacian- modified naïve Bayesian target models and 1-nearest- neighbor (1NN) similarity searching (target prediction)	Hit identification and target prediction of chemical screening using ChEMBL bioactivity data. Available at  http://mips.helmholtz- muenchen.de/hitpick/cgi- bin/index.cgi? content¼hitIdentification. html	[105, 106]
Chemputer	Modular robotic system equipped with AI	Automation of chemical synthesis and analysis	[107]
PotentialNet	Multistaged spatial gated graph CNN	Molecular property prediction like ADMET, solubility,  protein-ligand binding affinity, etc.	[108]
REINVENT	Open-source Python application; PyTorch as a deep learning engine, and RDKit version as a chemistry engine	De novo design of small molecules; publicly available at https://github. com/MolecularAI/Reinvent	[109]
AlphaFold	CNN	Predicts 3D structure of protein with high accuracy	[110]
DeepTox	DNNs comprising SVM, RF, and elastic nets	Prediction of toxicity of drugs and environmental chemicals	[111]
The Polypharmacology Browser (PPB2)	Combination of nearest neighbor searches and naïve Bayes	Prediction and used as a target prediction tool. It also computes ligand similarities. Available at https://ppb2.gdb.tools/	[112]
ORGANIC	GAN	Molecular generation tool used to create molecules with desired properties; inverse design chemistry	[113, 114]
DeepDDI	DNN	Prediction of drug–drug interactions (and drug–food constituent interactions)	[115]
CASE Ultra	QSAR and ML	Prediction of preclinical toxicity of potential molecules	[116]
ADMETlab	QSAR regression or classification models using		[117]

AI tool	AI approach	Application	Ref
	six different machine learning algorithms	Prediction of ADMET; available at http://admet. scbdd.com/
Mol-CycleGAN	GAN with reinforcement learning	Molecule design for a desired physicochemical or structural property	[118]

Applications of ANN in preformulation studies

 

AI tool	Formulation/preformulation characteristics	Input	Output	Outcome of study	Ref.
Kohonen’s SOMs	Tablets prepared by direct	Wetting time, water	Disintegration	Classified the disintegration	[146]
(ViscoverySOMine  software)	compression; 11 different	absorption ratio, particle	time of tablets	actions of test disintegrants
	disintegrants were tested for	size, morphological		into four distinct clusters
	disintegration of tablets	observation, swelling
		property, and relaxation time
ANN (CAD/Chem)	Polymer blends (HPMC, PVP, HPC, carrageenan, sodium alginate) in water for glass transition temperature	Matrix polymer composition	Glass transition temperatures, viscosity, water uptake	ANNs accurately predicted outputs with a low % error (0–8%) of prediction	[147]
BT algorithm and multiple regression	Tablets prepared by direct compression method for tensile strength	Particle size distribution, Hausner ratio, moisture content, elastic recovery, and molecular weight of 81 drugs	Tensile strength	BT model had high performance	[148]
ANN (Matlab 6.1) and regression model	Solubility of drugs in water– cosolvent mixtures	Experimental solubility of solutes in water–cosolvent systems (35 datasets)	Solubility	ANN was superior to the regression model	[149]
ANN	Hydrotropic solubilization of indomethacin in water	Experimental data, together with various known and computed  physicochemical properties	Solubility in water	In silico screening tool for drug/hydrotrope  systems using ANN	[150]
ANN and MLR models	Skin permeability of new chemical entities	Skin permeability, Abraham descriptors of R2 (excess molar refraction), the dipolarity/polarizability,  the overall or effective hydrogen-bond acidity and	Skin permeability	Better prediction of skin permeability with ANN	[151]

AI tool	Formulation/preformulation characteristics	Input	Output	Outcome of study	Ref.
		basicity, and the McGowan (215 datasets)
DNN model and LASSO models	Permeability of small drug- like molecules across lipid membranes	Molecular descriptors and fingerprints	Membrane permeability	DNN model using molecular fingerprints can help develop a more accurate mapping	[152]
MLP and SVM	Predicting CNS permeability of drug molecules	MW, surface area, volume, log P, HLB, CNS activity (+/ -), H 3d, H donor, H acceptor	CNS permeability	SVM algorithm was superior	[153]
ANNs, (BrainMaker Professional) and KNN	Pharmaceutical  fingerprinting of samples of L-tryptophan (LT) (API) on the basis of HPLC trace impurity pattern	899 data entries extracted from each HPLC chromatogram; 253 chromatograms	Classifier developed	ANN with 46 inputs was superior to all other classifiers with 93% accuracy	[154]
SVM; four different types of ANN, namely, backpropagation  (BPNN), genetic BPNN Mind Evolutionary  Algorithm- Based BPNN (MEA-BPNN), and Extreme Learning Machine (ELM)	Powder compactability of powder blends for tensile strength and brittleness	Raw material attribute inputs; Conc. of material for shell and core (% wt/v), type of material for core, shell	Tensile strength and brittleness index	ANN algorithms were more capable of handling convoluted and nonlinear patterns of dataset	[155]

Expert systems for screening of excipients and formulation designing

 

Expert system	Formulation/ dosage form	Application	Organization	Ref.
CAPEX	Hard gelatin capsules	Formulation designing and prediction of dissolution rate	University of Maryland Baltimore County	[171, 172]
ESFppop	Push-pull osmotic pump (ppop) of poorly water-soluble drugs	Predict composition of push-pull osmotic tablets and drug release	Shenyang Pharmaceutical University, China	[173]
SeDeM expert system	Matrix tablets of theophylline	SeDeM expert system conceived and applied to assess compressibility of powder mixtures	University of Barcelona, Spain	[174]
SeDeM expert system	ODTs	Screening of excipients on the basis of Index of Good compression (IGC) for preparing ODTs	University of Barcelona, Barcelona, Spain	[175]
SeDeM- ODT expert system	ODTs	New model that provides the Index of Good Compressibility and Bucodispersibility  (IGCB index) to assess fast in vitro disintegration of ODTs prepared by direct compression	Novartis Pharmaceutical- Spain and University of Barcelona, Barcelona, Spain	[176]
SeDeM expert system	Drug excipient powder blend	Assess suitability of theophylline and lactose blends for direct compression	University of Seville, Spain	[177]
SeDeM expert system	Matrix tablets of theophylline for sustained release	Assess suitability of biodegradable polyurethanes and theophylline blends for direct compression	University of Seville, Spain	[178]
SeDeM expert system	Medicated chewing gum tablets of lyophilized lysozyme	Assess powder blends for its suitability for direct compression	Goethe-University Frankfurt, Germany	[179]
SeDeM and SeDeM- ODT	Preformulation studies of pediatric ibuprofen ODT tablets	Compressibility and bucodispersibilty of ibuprofen-Ludiflash blends; optimized ODT tablets	University of Medicine and Pharmacy Tirgu Mureş, Romania	[180]

Applications of ANN in formulation development and optimization

 

AI tool	Formulation/dosage form	Inputs	Output	Outcome	Ref.
ANN-based expert system (PharmCAD expert system)	Ketoprofen solid dispersions (SD) and physical mixtures	7 inputs; type and preparation technology as well as qualitative and quantitative composition of SD and physical mixtures (PM)	Drug dissolution	ANNs functioned well as decision support system and data-mining tool	[184]
ANN-based expert system (PharmCAD expert system)	Solid dispersion	16 inputs; MW of drug and two carriers, amount of drug and two carriers, Connectivity Index (CI) of drug and two carriers, formulation type, preparation technology, cooing conditions, rpm paddle/basket, pH of dissolution media, time of dissolution	Amount of drug dissolved	PharmCAD expert system for deriving knowledge from empirical data	[185]
Fuzzy logic-based expert system	Freeze-dried peptide and protein-based formulations	Off coloring, image entropy, cake collapse, and light saturation were inputs	Quality of cake (quality attributes collapse, glassiness, uniformity, and color)	High-throughput formulation screening by image analysis	[186]
ANN and DNN model	ODTs	Molecular parameters of drug, amount of drugs, amount of excipients, type of encoded excipients, manufacturing  parameters, and disintegration time	Disintegration time	DNN performs well in all three datasets with over 80% accuracy	[187]
DNN, MLR, PLSR, SVM, ANNs, RF, k-NN		Molecular parameters of drug, amount of drugs,			[89]

AI tool	Formulation/dosage form	Inputs	Output	Outcome	Ref.
	Oral sustained release matrix tablets and fast disintegrating films	amount of excipients, type of encoded excipients, manufacturing  parameters, and disintegration time	In vitro characteristics; disintegration and drug release	DNN model as superior to other machine learning models
ANN model	Topical matrix patches of diclofenac sodium	Time, chitosan amount, and carrageenan amount	Drug release and the ex vitro skin permeation kinetics	•      ANN-predicted outputs with reasonable accuracy	[188]
•      INForm V.4 ANN for neural networks, FormRules V.3.32 for neurofuzzy logic, and INForm V.4 GEP	Ramipril tablets prepared by the direct compression	HPMC, lubricant type, lubricant concentration	Tablet weight, friability, disintegration time, dissolution	Support  decision-making processes; optimized formulation was within the design space	[189]
MLP (ANN Neural Power® version 3.1)	Mesalamine matrix tablets by wet compression	9 inputs; amount of excipients	Friability, thickness, hardness, weight variation, content uniformity, dissolution	ANN-aided optimized formulation	[190]
MLP and Box Behnken Design	Multiple-unit  prednisone pellet system	MCC concentration, SSG concentration, spheronization time and extrusion speed	Aspect ratio, drug release at different time points, yield	ANN was recommended as complement RSM for optimization (Box Behnken design)	[191]
Supervised MLP (STATISTICA 7.0 Neural Networks and MATLAB R2014b) and D-Optimal mixture design	Cross-linked polymeric ibuprofen printlets by digital light processing (DLP)	Amount of PEGDA, PEG 400, and water	In vitro drug release at different time points	Both ANNs performed better than D-optimal mixture design	[192]
A generalized regression neural network (GRNN) (TIBCO Statistica® Software), and self-	DLP-based 3D-printed tablets of atomoxetine	Data from 23 experiments; input variables were: tablet thickness and drug loading	Release rate after 15, 30, 60, 120, 240, and 360 min	ANN predictive models for atomoxetine release rate developed	[193]

    

AI tool	Formulation/dosage form	Inputs	Output	Outcome	Ref.
			Kawatika’s fitting parameters (a, 1/b) minitablets’ avg. weight, weight variation, and relative density

FDA-approved AI/ML-based devices

 

Medicinal field	Devices (company, date of approval)
Cardiology	Imbio RV/LV Software (Imbio, LLC, 2021) Caption Interpretation Automated Ejection Fraction Software (Caption Health, 2020) Eko Analysis Software (Eko Devices, Inc., 2020) AI-ECG Platform (Shenzhen Carewell Electronics Ltd., 2019) EchoGo Core (Ultromics Ltd., 2019) Arterys Cardio DL (ARTERYS, Inc., 2018) EchoMD (Bay Labs, Inc., 2018)
Endocrinology	Guardian Connect System (Medtronic MiniMed, Inc., 2018) DreaMed Advisor Pro (DreaMed Diabetes Ltd., 2018)
Radiology	MEDO-Thyroid (Medo.AI, 2021) LVivo Software Application (DiA Imaging Analysis Ltd., 2020) FastStroke, CT Perfusion 4D (GE Medical Systems SCS, 2020) TransparaTM (Screenpoint Medical B.V, 2019) Deep Learning Image Reconstruction (GE Medical Systems, LL, 2019) HealthPNX (Zebra Medical Vision Ltd., 2019) Advanced Intelligent Clear-IQ Engine (AiCE) (Canon Medical Systems Corporation, 2019) SubtleMR (Subtle Medical, Inc., 2019) AI-Rad Companion (Pulmonary) (Siemens Medical Solutions USA, Inc., 2019) EchoMD Automated Ejection Fraction Software (Bay Labs Inc., 2018) SubtlePET (Subtle Medical, Inc., 2018)
Neurology	Viz ICH (Viz. AI, inc., 2020) Accipiolx (MaxQ AI Ltd., 2018) Icobrain  (Icometrix,2018) ContaCT (Viz.AI, 2018) EnsoSleep (EnsoData, Inc., 2017)
Internal medicine	FerriSmart Analysis System (Resonance Health Analysis Services Pty Ltd, 2018)
Ophthalmology	IDx-DR (Digital Diagnostics, 2018)
Emergency Medicine	Critical Care Suite (GE Medical Systems, LLC., 2019) HelathPNX (Zebra Medical Vision Ltd., 2019) BriefCase (Aidoc Medical, Ltd., July 2018) OsteoDetect (ImagenTechnologies, Inc., 2018)
Oncology	QuantX (Quantitative Insights, Inc., 2020) Transpara™ (ScreenPoint Medical B.V., 2019) cmTriage (CureMetrix, Inc., 2019) ArterysMICA (Arterys, Inc., 2018) Arterys Oncology DL (Arterys Inc., 2018) Profound™ AI Software V 2.1 (CAD, Inc, 2018)

 Some recent collaboration of AI companies with pharmaceutical companies

 

AI company	AI platform	Major collaboration with pharmaceutical company	Date of collaboration	Use	Ref.
Exscientia	Centaur Chemist	Bayer	January 2020	Identify and optimize novel lead molecule for oncological and cardiovascular disease	[237]
		Sanofi	May 2017	To find bispecific small molecules for diabetes and comorbidities
		GSK	April 2019	Finding novel drug molecules for targeting pathways of chronic obstructive pulmonary disorders
Atomwise	AtomNet	Lilly	June 2019	To develop drugs on novel protein targets	[238]
Cyclia	MatchMaker	Bayer	November 2018	Pharmacokinetic property prediction and multitargeted drug design	[239]
		Merck	December 2018	Elucidate mechanism of action, safety profiles of investigational small molecules
Schrodinger		Bayer	January 2020	Codevelop de novo design technology to accelerate drug discovery	[240]
		AstraZeneca	September 2019	To develop advanced computing technology for drug discovery.
Insilico Medicine	Pharma.AI	GSK	August, 2017	To identify novel biological pathways	[241]
Iktos	Makya™	Pfizer	March 2021	De novo designing software for	[242]

 

AI company	AI platform	Major collaboration with pharmaceutical company	Date of collaboration	Use	Ref.
				multiparametric optimization
Biovista	COSS™	Astellas	December 2015	Identifying new indications for a number of undisclosed compounds	[243]
Numerate	Algorithm- driven drug discovery platform	Takeda	June 2017	Drug discovery for oncology, gastroenterology, and CNS disorders	[244]
Berg	bAlcis®	AstraZeneca	August 2017	Evaluation of novel targets for neurodegenerative disorders	[245]
		Sanofi	October 2017	Assess potential biomarkers for seasonal flu vaccine performance
Benevolent	Benevolent Platform®	AstraZeneca	April 2019	NN-based platform for treatment of chronic kidney disease and idiopathic pulmonary fibrosis	[246]
		Janssen	November 2016	License the rights to develop and manufacture clinical stage drug candidates

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