Open source software and web services for designing therapeutic

moleculesG. P. S. Raghava, Head Bioinformatics Centre, Institute of Microbial Technology, Chandigarh

Important Web Sites

Open Source Drug Discovery(OSDD) http://www.osdd.net/

CRDD Site: http://crdd.osdd.net/

Raghava’s Group: http://www.imtech.res.in/raghava/

Software Development for Drug Discovery

•Discovery of Drug by Public for Public

•Drugs for Disease Specific to Developing Countries (like India)

•Development of Drugs for diseases of poor persons

•Process of Discovery will be fast (few to many contributors)

•Academic institutes/universities and small industry may afford

Examples of open source software

• Operating Systems– Linux– FreeBSD, OpenBSD, and NetBSD

• Internet– Apache (> 50% of the world's web servers)– BIND: DNS for the entire Internet.– Sendmail (Most email servers) – OpenSSL (standard for secure communication)

• Programming Tools– Languages (Perl, Python, PHP)– GNU compilers and tools (GCC, Make)

The amount of fund required depends on the success rate at the clinical trial stage

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An overview of the workflow of in silico drug designing process

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Important Points

1. Source of Molecules (databases or repositories)2. Molecular Editors (editing & viewing existing molecules) 3. Analog Generators (software used to generate analogs) 4. Structure Optimization (Energy/geometry of molecules)5. Calculation of Molecular Descriptors 6. Chemical Similarity Search 7. Development of QSAR/QSPR Models 8. Classification and Clustering of Small Molecules 9. Docking Small Molecules in Macromolecules 10. Pharmacophore Tools/Search 11. Software for ADMET Techniques 12. Designing of Inhibitors 13. Major Initiatives towards affordable drugs

Databases and resources managing and hosting chemical compounds

Database Brief Description with URL

PubChemA comprehensive database of bioassays, compounds andsubstances (http://pubchem.ncbi.nlm.nih.gov/)

ChEMBLDatabase of drug like molecules(https://www.ebi.ac.uk/chembldb)

ZincMaintain commercially-available compounds for virtualscreening (http://zinc.docking.org/)

ChemDB Collection of small-molecules (http://cdb.ics.uci.edu/)ChemSpider A chemical database (http://www.chemspider.com/)

MMsINCCommercial compounds(http://mms.dsfarm.unipd.it/MMsINC/)

KEGGMaintain comprehensive information(http://www.genome.jp/kegg/)

SMPDB Small molecule Pathway database (http://www.smpdb.ca)HMDB Human Metabolites (http://www.hmdb.ca/)

PDBeChemDictionary of chemical components refered in PDB entries(http://www.ebi.ac.uk/pdbe-srv/pdbechem/)

PDB-BindBinding affinity information for PDB Ligands(http://sw16.im.med.umich.edu/databases/pdbbind/index.jsp)

BindingDB Binding affinity of PDB Ligands (http://www.bindingdb.org/)

NCISmall molecules related to cancer(http://cactus.nci.nih.gov/ncidb2.1/)

List of major molecular editors, frequently used for drawing and editing molecules

Editors Brief description

BKchemPython based free 2D molecule editor(http://bkchem.zirael.org/)

PubChemSketcher[117]

A web-based tool for sketching, integrated inPubChem(http://pubchem.ncbi.nlm.nih.gov/edit2/index.html)

ChemSketch

ACD/ChemSketch Freeware is a free software fordrawing chemicals(http://www.acdlabs.com/resources/freeware/chemsketch/ )

JChemPaint

Editor for 2D chemical structures(http://jchempaint.github.com/)

AccelrysDraw

Draw and edit complex molecules, no fee foracademic community(http://accelrys.com/products/informatics/cheminformatics/draw/index.html)

XDrawChem

Molecule drawing program(http://xdrawchem.sourceforge.net/)

MedChemDesigner

Drawing molecules and integration with ADMETproperty.(http://simplus-downloads.com/)

JMEJME Molecular Editor(http://www.molinspiration.com/jme/)

Analogs generation softwaresSoftware Brief description

SmiLib [118]

Enumerates combinatorial libraries with very highrate(http://gecco.org.chemie.uni-frankfurt.de/smilib/)

GLARE[119]

Generate combinatorial library(http://glare.sourceforge.net/)

Librarysynthesizer

Virtual chemical enumeration(http://tripod.nih.gov/?p=370)

CLEVER[120]

Chemical Library Editing, Visualization andEnumerating Resource (http://datam.i2r.a-star.edu.sg/clever/)

Newlead[121]

Generate of combinatorial library from bioactiveconformations(http://www.ccl.net/cca/software/MAC/index.shtml)

List of software and web servers used for structure optimization of molecules

Software Brief description

Openbabel[38]

The Open Source Chemistry Toolbox (http://openbabel.org/)

Frog [39]Generation of free online drug conformation(http://bioserv.rpbs.jussieu.fr/cgi-bin/Frog)

SMI23D[122]

Generation of 3D(http://www.chembiogrid.org/cheminfo/smi23d/)

Cyndi [123]Generate geometrically extended or compact conformations(http://www.biomedcentral.com/1471-2105/10/101/additional/)

BalloonConformer Ensembles(http://web.abo.fi/~mivainio/balloon/index.php)

DG-AMMOS[41]

Generate 3D conformation using distance geometry(http://www.mti.univ-paris-diderot.fr/fr/downloads.html)

TINKER[124]

Software Tools for Molecular Design(http://dasher.wustl.edu/tinker/)

MOPAC Semiempirical quantum chemistry program(http://openmopac.net/)

Important software and webserver for computing molecular descriptorsSoftware Brief description

PowerMV[125]

Window based calculation of descriptors

(http://nisla05.niss.org/PowerMV/index.html)

PaDEL[126]

Fingerprints calculation(http://padel.nus.edu.sg/software/padeldescriptor)

Joelib Descriptor calculation software(http://sourceforge.net/projects/joelib)

MOLD2[45]

Calculating descriptors from a two-dimensionalchemical structure (http://www.fda.gov/ScienceResearch/BioinformaticsTools/Mold2/default.htm)

Afgen Fragment-based descriptors(http://glaros.dtc.umn.edu/gkhome/afgen/overview)

ISIDA-fragmentor

Calculate of Substructural Molecular Fragmentsand ISIDA Fragments(http://infochim.u-strasbg.fr/spip.php?rubrique49)

ODDesripotrs

Simple java-based command level tool fordescriptor calculation(http://www.softpedia.com/get/Science-CAD/ODDescriptors.shtml)

CDK [127] Chemistry Development Kit(http://cdk.sourceforge.net)

Filter-it Filter-it is used for calculating descriptors andfiltering drug-like molecules. (http://silicos-it.com/software/software.html)

MODEL[128]

A webserver for molecular descriptor based upon3D structure http://jing.cz3.nus.edu.sg/cgi-bin/model/model.cgi

Similarity search algorithms and their web links

Software DescriptionJCsearch JC search used for searching similar structure,

substructureas well as super structure from a givendatabase.(http://www.chemaxon.com/jchem/doc/user/Jcsearch.html)

PubChem PubChem provide the facility to search similar chemical inPubChem database using PubChem based binaryfingerprints. (http://pubchem.ncbi.nlm.nih.gov/search/)

SIMCOMP[129]

Chemical structure similarity search against KEGGCOMPOUND, KEGG DRUG, and other databases.SIMCOMP is based on 2D graph representation.(http://www.genome.jp/tools/simcomp/)

SUBCOMP[129]

SUBCOMP is based on bit-string representation ofchemical structures.(http://www.genome.jp/tools/subcomp/)

SMSD[130]

SMSD is a Java based software library for calculatingMaximum Common Subgraph (MCS) between smallmolecules. This will help us to find similarity/distancebetween two molecules. (http://www.ebi.ac.uk/thornton-srv/software/SMSD/)

Machine learning and feature selection techniques in cheminformatics

S o f t w ar e

B r i ef de s c ri ption

S o f t w a r e us e d f o r deve l oping QS A R mod e l

S VM

S V M i s a su p e rvi s e d l ear n i n g t ec hn i q u e , u s e d f orc l as s i fi ca t io n a nd r egr e ss io n a n aly s i s . T h e Q S A Rm o d el s ca n b e op tim ize d u s i n g d iff e r e nt SV Mp ara m e te r s a n d k er n e l s .( htt p :/ / w w w . cs . co r n e ll . e d u / Peo p l e / tj / s v m _l i gh t/ )

A N N

A N N is b as e d o n s u p e r vi s e d l ear n i n g, u n su p e rvi s e dl e ar n i n g a nd r e i nf orc em e nt l e ar n i n g. S NN S(St u tt ga rt N e u ral N e t wo r k S i mu la t or ) i s a f re e

s o ft wa r e s i mu la t o r f or n e u ral n e t wo r k s.( htt p :/ / w w w. ra. c s . u ni- t u e bi ng e n . d e / S N NS / )

k N N

T h e k -n ear e st n e i g h bor algori thm ( k -NN) i s a m e th o d

f o r cla ss i f yi n g o bj e ct s b ase d on c l os e s t t rai n i n gexa mp l e s . T i M B L i s a n o p e n s o u r c e s o ft war e p ac k age

i mp l em e nt i n g k-n ea r e st n e i g h bor cla ss i f ica ti on .( htt p :/ /i l k .u v t . n l/ tim b l / )

W e k a

[ 53 ]

W e k a i s a coll e c t io n o f vi su ali z a t io n t oo l s a n dalgo r i thm s f o r da t a ana l ys i s a n d p r e d ic ti ve m o d e l i n g,It co nt ai ns l i b S V M , S M O , Na i veBaye s, LM T ,R an d o m Fo r e st et c lear n i n g algor it h ms.( htt p :/ / w w w . cs .w ai k a t o.ac .n z/ ~m l/ w e k a/ )

F ea t u r e S e l ec t ion techn i que s

W e k a

W e k a i s a po pu la r java b as e d t oo l u s e d i n fe a t ur es el e c t io n . T h e r e a r e vario us fe a t ur e s e le ct io n

m e th o d s a n d eval u a t or s a r e availa bl e i n W e k ap ac k age .( htt p :/ / w w w . cs .w ai k a t o.ac .n z/ ~m l/ w e k a/ )

R ap i d min er

R ap i d M i n er i s a f r e e ly av ai l ab l e so ftw a r e . Itco nt ai ns B r u te f o r c e , For w ar d s e l ec ti on an dBac kw ar d e l i m i n a t io n algor it h ms for f e a t ur e

s el e c t io n .( htt p :/ /ra p i d- i . co m / c on te n t/ vie w /181 / 190/ )

O r ang e or n gF SS ( Or ange .f ea t u r e. s e l ec t ion ) m odule p r ovi d e sf ea tu r e s e le ct io n f ac i l i t i e s . I t co nt ai ns a tt M e as u r e ,

List of chemical clustering tools and their web addresses

Software Brief descriptionChemMine Chemical clustering and analysis

(http://chemmine.ucr.edu/)ChemMineR It is R based open source chemical clustering tool.

(http://manuals.bioinformatics.ucr.edu/home/chemminer)

Jcluster ChemAxon Cluster(http://www.chemaxon.com/products/jklustor/)

ChemBioserver [57]

Chemical clustering webserever(http://bioserver-3.bioacademy.gr/Bioserver/ChemBioServer/)

Different types of pharmocophore searching softwares

Softwares Brief descriptionPharmapper[69]

Ligand based Pharmacophore search(http://59.78.96.61/pharmmapper/)

PharmaGist[70]

Ligand based Pharmacophore search(http://bioinfo3d.cs.tau.ac.il/PharmaGist/)

Pharmer[71]

Both PDB and ligand based pharmacophore search(http://smoothdock.ccbb.pitt.edu/pharmer/)

ZincPharma[133]

Both PDB and ligand based pharmacophore search(http://zincpharmer.csb.pitt.edu/pharmer.html)

Boomer Pharmacokinetic drug monitering(http://www.boomer.org/)

CyberPatient

A software for pharmacokinetic simulations(http://www.labsoft.com/www/software.html)

PKfit A tool for pharmacokinetic modeling(http://cran.csie.ntu.edu.tw/web/packages/PKfit/index.html)

JPKD Therapeutic drug monitoring(http://pkpd.kmu.edu.tw/jpkd/)

tdm Therapeutic drug monitoring(http://pkpd.kmu.edu.tw/tdm/)

mobilePK (http://pkpd.kmu.edu.tw/mobilepk/)

Some open source initiatives for drug discovery with their research area

Project Research AreasDrugs for NeglectedDiseases Initiative

Sleeping sickness, visceral leishmaniasis,Chagas disease (http://www.dndi.org/)

Infectious DiseaseResearch Institute

Tuberculosis, leishmaniasis, Chagasdisease, malaria, leprosy and Buruliulcer (http://www.idri.org/)

Blue Obelisk Provides open source cheminformaticstools.(http://sourceforge.net/apps/mediawiki/blueobelisk/index.php?title=Main_Page)

OSDD Promoting open source for neglecteddisease. (http://www.osdd.net/)

OpenTox Toxicology (http://www.opentox.org/)Global Alliance forTB

Tuberculosis (http://www.tballiance.org/)

Platform for Discovering and Designing of Drug Molecules

Load Data

Calculate descriptors

• CDK

• Padel

ADMET Properties

• MetaPred

• ToxiPred

• DrugMint

Screening Databases

• FDA molecules

• PUBChem

• Zinc datbase

Format coversion

• SMILE

• MOL

• SDF

• Babel

Pharmacophore