pharmacophore model development for the identification of

Abstract

BACKGROUND

Methods & Results Conclusion

Acknowledgements

References

Pharmacophore modeling has become anintegrated part of drug discovery. The workdescribed herein focuses on the use of ligand-based pharmacophore modeling to identifynovel acetylcholinesterase inhibitors againstAlzheimer’s disease. From a small training setof known dual inhibitors of the Torpedocalifornica acetylcholinesterase (TcAChE), wegenerated a series of ligand-basedpharmacophore models using the MolecularOperating Environment (MOE) software1. Themodels were further used to screen a lead-likesubset of the ZINC database2. The top 25molecules were virtually screened against theTcAChE three-dimensional structure usingMolegro Virtual Docker3 in order to prioritizehits for experimental testing.

Using a combination of ligand based andstructure based drug design approacheswe have identified structurally diversedual inhibitor candidates for TcAChE.

The national BBSI program(http://bbsi.eeicom.com) is a jointinitiative of the NIH-NIBIB and NSF-EEC, and the BBSI @ Pitt issupported by the National ScienceFoundation under Grant EEC-0234002.

1. Lin A. Overview of pharmacophoreApplication in MOE. Chemica Computinggroup. http://www.chemcomp.com/journal/ph4.htm

2. Irwin and Stoichet. J. Chem. Info. Model.(2005); 45(1): 177-182

3. Molegro Virtual Docker. www.molegro.com

4. Xu. et al. induced fit or preexistingequilibrium dynamics? Protein Science(2008), 17: 601-5

A caption, centered.

• Dr Jeffry Madura

• Kennesaw State University

Pharmacophore Model Development for the Identification of Novel Acetylcholinesterase Inhibitors

Edwin Kamau1,2 and Gabriela Mustata3

1Bioengineering & Bioinformatics Summer Institute, Department Computational Biology, University of Pittsburgh, Pittsburgh, PA 152602Department of Chemistry & Biochemistry, Kennesaw State University, Kennesaw, GA, 301443 Department Computational Biology, University of Pittsburgh, Pittsburgh, PA 15260

Acetylcholinesterase

Multifunctional enzyme

Function: Termination of nerve

impulses of acetylcholine

origin

Promotes production of

β-Amyloid protein

Associated with pathogenesis of

Alzheimer's Disease (AD)‏

Impairs the cholinergic system

Promotes formation of plaques

Alzheimer's Disease Available drugs only able to treat certain stages only

Structure4

Peripheral Anionic Site (PAS)

Trp 279

Catalytic Anionic Site (CAS)

Trp 84

Lining of aromatic residues

55 X-ray structures with

bound ligands Xu. et al. 2008,17:601-5

Drug-like Molecule Rule

Ligand-Based Drug

Design (MOE)

Start

Training set

Pharmacophore Model Development

Pharmacophore Model Validation

3D Database Screening

Top 25 Hits

Structure-Based Drug

Design (Molegro)

(TcAChE)

Top 5 Hits

Experimental

Assay(TBD)

SAR Data Set of AChE Dual Inhibitors

Green borders: test setRed border: training set;

Pharmacophore Queries

3 Queries Generated:

1.4

HYD| ARO| 3 VOLS

1.4

Donepezil

HYD| ARORef_No _Vol

HYD| ACC|DON| ARO

1.74

Consensus

Features a

Donepezil

All training set

molecules

Molecule(s)Tolerance

RadiusQuery

ReF_Vol

a ACC,hydrogen-bond acceptor; DON, hydrogen-bond donor; HYD,hydrophobic, ARO, ring aromatic, Vols, excluded volumes

Reference queries with and without excluded volumes generated using Donepezil. Meshed spheres represent pharmacophoric features volumes in both queries. Solid spheres (red, blueand cyan represent excluded volumes

Consensus query generated from flexible aligned training set. Meshed spheres are the pharmacophore features (Aro, Acc, Hyd, Don) . Molecules matching the features satisfied the query and were therefore hits

Bis5 tacrineBis10 HupyridoneAminoquinoline28Bw284c51 DonepezilDecamethonium

Search Results and Sorting

Query Ref:Vol ef:No Vol Consensus

Number of hits 211 378 329

Sort top 100 100 100 100

Common hits 68

Selection based on Lowest rmsd value

25

Sorted Hits (2D Structures)

3D Database Search

Docking Results (Top 5 solutions are highlighted)

Virtual Screening

Binding mode of E2020 (Donepezil) and ZINC3785268.

Future Work Virtually screen the remaining lead-like

compounds of the ZINC database

Prioritize hits for experimental testing (i.e. binding free energy; types of interactions in the active site)‏