Optimizing Your Leads for Potency AND Drug-Likeness - …...Optimizing Your Leads for Potency AND...

Optimizing Your Leads for Potency AND Drug-Likenessor “How to Have it All”

Optibrium UGM at the ACS Fall Meeting 2012Dr Robert Scoffin

CEO

> About Cresset> Cresset Technology

> Science

> Applications

> Example

Agenda

About Cresset

> Cresset supplies software tools and consulting services to life sciences customers

> Particular focus on molecular design within drug discovery

> Users include:> Medicinal chemists

> Computational chemists

> Patent officers

Cresset Summary

> Cresset’s solutions enable:> Deeper understanding of actual drug activity

> Prediction of likely activity for novel compounds

> Unique underlying technology provides a much more accurate representation of drug-protein interactions than other computational approaches

> Proven techniques through an extensive portfolio of successful consulting projects

Cresset Summary

NN

Br

F FF

SH2NOO

Example Customers

Cresset Technology

NN

Br

F FF

SH2NOO

Condensed representation of electrostatic, hydrophobic and shape properties (“protein’s view”)

> Molecular Field Extrema (“Field Points”)

Field Points

3D Molecular Electrostatic

Potential (MEP)

Field Points= Positive = Negative= Shape= Hydrophobic

2D

NN

Br

F FF

SH2NOO

Field Points - an analogy

2D drawing very useful for synthesis planning, quick recognition of structural type, IP protection, etc. Not particularly useful for understanding shape and interactions with

proteins.

3D representation of shape and electronic properties very useful for understanding

complex characteristics and interactions. Not useful for rapidly analyzing large numbers of

molecules to e.g. find matches.

Field point representation allows for rapid analysis of collections of molecules, whilst

retaining the ability to understand shape and electronic properties.

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H-bond donor

H-bond acceptor

Hydrophobes

Aromatic cloud

‘H acceptor’

Aromatic in-plane ‘H donor’

-ve ionic

+ve ionic

“Stickiest” surfaces(high vdW)

N

NH

O

O

OH H

H

Explanatory Power of Fields

Field points give you new insights into your molecule

= Positive = Negative= Shape= Hydrophobic

Field point size show importance

> Field patterns from Cresset’s proprietary XED force field reproduce experimental results

XEDs Make Fields Work

Interaction of Acetone and Any-OH from small

molecule crystal structures

Experimental Using XEDs Not using XEDs

XED adds p-orbitals to get better representation of atoms

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Information Provided by Fields

Field points give you new insights into your molecule

Experimental

Fields

Structure

13

Bioisosteres – PDE III

Bioisosteres

Biologically relevant method for comparing molecules

> Ligand-based virtual screening> Diverse lead like hits> Large library design> HTS rescue

Cresset Applications

> Expert computational tool for SAR, QSAR and design

> Build predictive models> Improve design

> Singles> Libraries

> Bioisostere generation and replacement> New chemistry directions> Patent protection> Patent busting

> Med.Chem. tool for SAR and design> Relate chemical series> Understand shape and electrostatic

properties> Play models built in forgeV10 to predict

activity or properties

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forgeV10 – Alignment/Similarity/[Q]SAR

Viagra – Levitra

Viagra(Sildenafil)

Levitra(Vardenafil)

> Molecule treated as single conformation> e.g. Ligand from protein crystal structure

> Pharmacophore hypothesis

> Includes multiple pre-aligned single conformations

> Molecule treated as conformation population> All other cases

> Conformations generated where necessary

> Results for all conformations concatenated together

Handling Conformation

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sparkV10 – Bioisostere Replacement

Viagra(Sildenafil)

O

S

OO

N

H+N

O

O

N

HN

N

N

Novartis compound – 100nM

#1 Result

Example: SARS PLpro

> Severe Acute Respiratory Syndrome (SARS)> Caused by a viral infection

> Viral DNA encodes for a polyprotein which then cleaves into multiple components, including several proteases which further process the polyprotein into active components (and also play a role in the release of viral particles from the infected cell)

The Target

> PLpro (Papain-like protease) is one of the key proteases in this process.

> Crystal structures available with bound ligands from 2 series of compounds> Structurally related (PDB entries 3E9S and 3MJ5)

> Small number of analogues> Challenge to see if we can use 3D-QSAR for small data sets

The Target

> Series 1 (3E9S)

> Series 2 (3MJ5)

Compound Series

Example Alignment

Model

PLS Components = 3 RMSE = 0.36 RMSEP = 0.77

> First series has good binding, but a problem is highlighted around the amide oxygen

> Replace in second series with +ve contribution

Med. Chem. Directions?

> Able to build a predictive 3D-QSAR model based on small number of analogues

> Model was able to retrospectively predict improvements which were actually made

Summary

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Thank you!

rob@cresset-group.com