Transcript Document

Open source software and web services
for designing therapeutic molecules
G. 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
Qu i c k T i m e ™ a n d a
Gra p h i c s d e c o m p re s s o r
a re n e e d e d to s e e th i s p i c t u re .
An overview of the workflow of in
silico drug designing process
Qu i c k T i m e ™ a n d a
Gra p h i c s d e c o m p re s s o r
a re n e e d e d to s e e th i s p i c t u re .
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
A comprehensive database of bioassays, compounds and
PubChem
substances (http://pubchem.ncbi.nlm.nih.gov/)
Database of drug like molecules
ChEMBL
(https://www.ebi.ac.uk/chembldb)
Maintain commercially-available compounds for virtual
Zinc
screening (http://zinc.docking.org/)
ChemDB
Collection of small-molecules (http://cdb.ics.uci.edu/)
ChemSpider A chemical database (http://www.chemspider.com/)
Commercial compounds
MMsINC
(http://mms.dsfarm.unipd.it/MMsINC/)
Maintain comprehensive information
KEGG
(http://www.genome.jp/kegg/)
SMPDB
Small molecule Pathway database (http://www.smpdb.ca)
HMDB
Human Metabolites (http://www.hmdb.ca/)
Dictionary of chemical components refered in PDB entries
PDBeChem
(http://www.ebi.ac.uk/pdbe-srv/pdbechem/)
Binding affinity information for PDB Ligands
PDB-Bind
(http://sw16.im.med.umich.edu/databases/pdbbind/index.jsp)
BindingDB Binding affinity of PDB Ligands (http://www.bindingdb.org/)
Small molecules related to cancer
NCI
(http://cactus.nci.nih.gov/ncidb2.1/)
List of major molecular editors, frequently used
for drawing and editing molecules
Editors
Brief description
Python based free 2D molecule editor
BKchem
(http://bkchem.zirael.org/)
PubChem A web-based tool for sketching, integrated in
Sketcher PubChem
(http://pubchem.ncbi.nlm.nih.gov/edit2/index.html)
[117]
ACD/ChemSketch Freeware is a free software for
ChemSk e drawing chemicals
tch
(http://www.acdlabs.com/resources/freeware/chemsket
ch/ )
JChemPa Editor for 2D chemical structures
int
(http://jchempaint.github.com/)
Draw and edit complex molecules, no fee for
academic community
Accelrys
Draw
(http://accelrys.com/products/informatics/cheminfo
rmatics/draw/index.html)
XDrawC Mo lecule drawing progra m
hem
(http://xdrawchem.sourceforge .net/)
MedChe Drawing molecules and integration with ADMET
m
property.
Designer (http://simplus-down loads.com/)
JME Molecular Ed itor
JME
(http://www.molinspir ation .com/jme/)
Analogs generation softwares
Software
Brief description
Enumerates combinatorial libraries with very high
SmiLib [118]
rate
(http://gecco.org.chemie.uni-frankfurt.de/smilib/)
GLARE
Generate combinatorial library
[119]
(http://glare.sourceforge.net/)
Library
Virtual chemical enumeration
synthesizer (http://tripod.nih.gov/?p=370)
Chemical Library Editing, Visualization and
CLEVE R
Enumerating Resource
[120]
(http://datam.i2r.a-star.edu.sg/clever/)
Generate of combinatorial library from bioactive
Newlead
conformations
[121]
(http://www.ccl.net/cca/software/MAC/index.shtml)
List of software and web servers used for
structure optimization of molecules
Software
Openbabel
[38]
Frog [39]
SMI23D
[122]
Cyndi [123]
Brief description
The Open Source Chemistry Toolbox (http://openbabel.org/)
Generation of free online drug conformation
(http://bioserv.rpbs.jussieu.fr/cgi-bin/Frog)
Generation of 3D
(http://www.chembiogrid.org/cheminfo/smi23d/)
Generate geometrically extended or compact conformations
(http://www.biomedcentral.com/1471-2105/10/101 /additional/)
Conformer Ensembles
(http://web.abo.fi/~mivainio/balloon/index.php)
DG-AMMOS Generate 3D conformation using distance geometry
[41]
(http://www.mti.univ-paris-diderot.fr/fr/downloads.html)
TINKER
Software Tools for Mole cular Design
[124]
(http://dasher.wustl.edu/tinker/)
MOPAC
Semiempirical
quantum
chemistry
program
(http://openmopac.net/)
Balloon
Important software and webserver for
computing molecular descriptors
So ftwa re
PowerMV
[125]
PaDEL [12
6]
Joelib
Brief de s cription
Window
based
calculation
of
descript ors
(http://nisla05 .niss.org/Po werMV/index.html)
Fingerprints calculation
(http://padel.nus.edu .sg/software/padeldescript or)
Descriptor calculation software
(http://sourceforge .net/projects/joelib)
MOLD2
Calculating descript ors from a two-dimensional
[45]
chemical structureÊ
(http://www.fda.gov/ScienceResearch/Bioinformati
csTools/Mold2/default.htm)
Afgen
Fragment-based descript ors
(http://glaros.dt c.umn.edu/gkhome/afgen/overview
)
ISIDACalculate of Substructural Molecular Frag ments
fragmentor and ISIDA Frag ments
(http://infochim.u-strasbg.fr/spip.php?rubriqu e49)
ODDesripo Simple java-based co mmand level tool for
trs
descriptor calculation
(http://www.softpedia.com/get/ScienceCAD/ODDescript ors.shtml)
CDK [127] Chemistry Developm ent Kit
(http://cdk .sourceforge .net)
Filter-it
Filter-it is used for calculating descriptors and
filtering drug-like molecules. (http://silicosit.com/software/software.html)
MODEL [1 A webs erver for molecular descript or based upon
28]
3D structure http://jing .cz3.nus.edu.sg/cgibin /model/model.cgi
Similarity search algorithms and their web links
Software
JCsearch
Description
JC search used for searching similar structure,
substructureas well as super structure from a given
database.
(http://www.chemaxon.com/jchem/doc/user/Jcsearch.html)
PubChem PubChem provide the facility to search similar chemical in
PubChem database using PubChem based binary
fingerprints. (http://pubchem.ncbi.nlm.nih.gov/search/)
SIMCOMP Chemical structure similarity search against KEG G
[129]
COMPOUND, KEGG DRUG, and other databases.
SIMCOMP is based on 2D graph representation.
(http://www.genome.jp/tools/simcomp/)
SUBCOMP SUBCOMP is based on bit-string representation of
[129]
chemical structures.
(http://www.genome.jp/tools/subcomp/)
SMSD
SMSD is a Java based software library for calculating
[130]
Maximum Common Subgraph (MCS) between small
molecules. This will help us to find similarity/distance
between two molecules. (http://www.ebi.ac.uk/thorntonsrv/software/SMSD/)
Machine learning and feature selection
techniques in cheminformatics
S o ftw a
re
B r i ef de s c ri ption
S o f t w a r e us e d f o r deve
QS
A R
mod
e l
S V M
is 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 or
c l as s i f i ca t io n
a nd
r egr e ss io n
a n aly s i s .
T h e
Q S A R
m o d el s
ca n
b e
op tim ize d
u s in g
d if f e r e nt
SV M
p 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
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 d
l 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 m u la t or )
is
a f
re e
s o f t wa r e s i m u 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 / )
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
fo 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 g
exa m p l e s . T i M B L i s a n o p e n s o u r c e s o f t war e p ac k age
i m p 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 ek a
is
a
coll e c t io n
o f
vi su ali z a t io n
t oo l s
a n d
algo 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
lib S V M ,
S M O ,
Na i veB aye
s,
LM T ,
R an d o m Fo r e st et c lear n i n g algor
it h m s.
( 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
S VM
A N N
k N N
W ek a
[ 53 ]
W e k a i s a po
pu la r java
b as e d t oo l u s e d
s el e c t io n .
T h ere
a re
vario
us
f e a t ur e
m e th o d s
a n d
eval u a t or s
a re
availa
bl e
p ac k age .
( htt p :/ / w w w . cs .w ai k a t o.ac .n z/ ~m l/ w e k a/ )
W ek a
R ap i d m i
n er
O r ang
l oping
e
in
f e a t ur e
s e le ct io n
in
W ek a
R ap i d M i n er
is
a
f r e e ly
av ai l ab l e
so f tw a r e .
It
co nt ai ns
B r u te
fo rc e ,
For w ar d
s e l ec ti on
an d
B ac kw ar d
e l i m i n a t io n
algor
it h m s
f or
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/
)
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 s
List of chemical clustering tools and
their web addresses
Software
Brief description
ChemMine Chemical clustering and analysis
(http://chemmine.ucr.edu/)
ChemMineR It is R based open source chemical clustering tool.
(http://manuals.bioinformatics.ucr.edu/home/che
mminer)
Jcluster
ChemAxon Cluster
(http://www.chemaxon.com/products/jklustor/)
ChemBioser Chemical clustering webserever
ver [57]
(http://bioserver3.bioacademy.gr/Bioserver/ChemBioServer/)
Different types of pharmocophore
searching softwares
Softwares
Pharmapper
[69]
PharmaGist
[70]
Brief description
Ligand based Pharmacophore search
(http://59.78.96.61/pharmmapper/)
Ligand based Pharmacophore search
(http://bioin fo3d.cs.tau.ac.il/PharmaGist/)
Pharmer
[71]
Both PDB and ligand based pharmacophore search
(http://smoothdock.ccbb.pitt.edu/pharmer/)
ZincPharma Both PDB and ligand based pharmacophore search
[133]
(http://zincpharmer.csb.pitt.edu/pharmer.html)
Boomer
C ybe r
Patien t
PKfit
JPKD
tdm
mobi lePK
Pharmacokinetic drug monitering
(http://www.boomer.org/)
A software for pharmacokinetic simulations
(http://www.labsoft.com/www/software.html)
A tool for pharmacokinetic modeling
(http://cran.csie.ntu.edu.tw/web/packages/PKfit/index.html)
Therapeutic drug monitoring
(http://pkpd.kmu.edu.tw/jpkd/)
Therapeutic drug monitoring
(http://pkpd.kmu.edu.tw/tdm/)
(http://pkpd.kmu.edu.tw/mobilepk/)
Some open source initiatives for drug
discovery with their research area
Project
Drugs for Neglected
Diseases Initiative
Infectious Disease
Research Institute
Blue Obelisk
OSDD
OpenTox
Global Alliance for
TB
Research Areas
Sleeping sickness, visceral leishmaniasis,
Chagas disease (http://www.dndi.org/)
Tuberculosis, leishmaniasis, Chagas
disease, malaria, leprosy and Buruli
ulcer (http://www.idri.org/)
Provides open source cheminformatics
tools.
(http://sourceforge.net/apps/mediawiki/b
lueobelisk/index.php?title=Main_Page)
Promoting open source for neglected
disease. (http://www.osdd.net/)
Toxicology (http://www.opentox.org/)
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