vls
DESCRIPTION
Virtual library screening strategiesTRANSCRIPT
S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician
Virtual library screening (VLS) in the Virtual library screening (VLS) in the Drug Discovery ProcessDrug Discovery Process
Molecular Modeling & Drug Design
S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA
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Outlines of the Presentation
1.Virtual Library Screening (VLS)
2.VLS Paradigm
3.Small molecule virtual libraries
4.Target selection
5.Binding site identification
6.Docking
7.Evaluation
8.ORVIL-ORganic Virtual Library (MY WORK)
Virtual screening
Virtual screening : a computational approach to
assess the interaction of an in silico library of small
molecules and the structure of a target macromolecule to rapidly identify new drug leads.
MeritsMeritsComputationalOnly high scoring ligands goes to assay
DemeritsDemeritsMolecular Complexity/DiversityFalse PositivesSynthesis Issue
VLS Paradigm
Library
Diverse Compounds, Synthetically accessible compounds
Target
Protein, Structure Determination Method
ADME, Pharmacophore
Interaction Site
Docking
Scoring & Evaluation
Lead Optimization
Small Molecule Virtual Libraries
Descriptors for chemical libraries (evaluate how much of chemical space isSampled ) = diversity of a given library Structural properties: VDW, electrostatic, H-bond donor/acceptor = energetically favorable contactsSimilarity/Dissimilarity Measures:Tanimoto Coefficient
PubChem, CCD, ZINC, NCI, ACD, chEBI, Drug Bank
Tanimoto Coefficient
N
HN
O
N
S
O
OH
Cl
ClO H
N S
N
OHO
NA is the number of features in A, NB is the number of features in B, and NAB is the number of features common to A and B.
5 5 4
= 4/(5+5-4)
=0. 67
ADME/T properties
Lipinski’s RO5 and Ghose et al, 1999 profiling for druglikeness
MW < 500 better absorption and low level of allergic reactions
Hydrogen bond donors and acceptors < 5 and 10
circumvent non-specific binding
logP value < 5 low level of toxicity, non-specific binding and possible oral administration
logD pH (7.4) > 0 An indicator of lipophilicity of a drug; high level of metabolic clearance by P450 enzymes of liver were expected
Topological polar surface area (TPSA) > 60 Å2 and < 140 Å2
a high possibility of complete absorption
e.g.QikProp,FAF-Drugs,ACDLabs Toxicity Analysis Toolkit
Pharmacophore Mapping
Ensemble of steric and electronic features required for interaction of ligand with biological target to triggers a biological response
PHASE
ReScore
DaylightH HBD HBA R
Query
Database
HO
H3C
H3C
HOCH3
CH3
OH
Target selection
Protein’s as Target :
XRD, NMR,
Homology Modeling
PDB,
Swiss Modeler,
Modeller 9v7,
WHATIF
Human Estrogen Receptor (2P7Z)
Ligand Binding Site
Modulate Protein’s Function
SiteMap,CastP
Binding Site Identification
3-Hydroxy Tamoxifen (Co-crystallized ligand)
The library must be docked
into the target site and evaluated for goodness-
of-fit.
1) docking – the search for the conformation and configuration of the ligand in the binding site
2) scoring – the evaluation of the interaction energy between
the target and ligand
Docking Docking of CDK6 Analogue
Docking and in silico Bioavailability Analysis of CDK6 Flavonol Inhibitors and its Analogues for Acute Lymphoblastic Leukemia. (Under Review: Journal of Computational Intelligence in Bioinformatics)
Glide,HEX 6,AutoDock,FlexX,DOCK 6.0,ArgusLab,GOLD
The scoring process evaluates and ranks each ligand pose in the target site
Energetically FavorableGibb’s EnergyH-Bond FormationOther Scores
The GScore is a combination of different parameters.
GScore = 0.065 * van der Waal energy + 0.130 * Coulomb energy + Lipophilic term + Hydrogen-bonding term + Metal-binding term + Buried polar groups penalty + Freezing rotatable bonds penalty + Active site polar
interactions.
Scoring & Evaluation