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