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Contents Vol 63(3)

Binding Mode Prediction of PDE4 Inhibitors: A Comparison of Modelling Methods

Diana S. Neale A , Philip E. Thompson A , Paul J. White A , David K. Chalmers A , Elizabeth Yuriev A and David T. Manallack A B
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A Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia.

B Corresponding author. Email: David.Manallack@pharm.monash.edu.au

Australian Journal of Chemistry 63(3) 396-404 https://doi.org/10.1071/CH09463
Submitted: 1 September 2009  Accepted: 12 February 2010   Published: 26 March 2010

Abstract

Molecular modelling is widely used in support of medicinal chemistry programs, with several theoretical approaches used in attempts to expedite drug discovery. In this study, three methods – molecular docking (Glide), shape similarity (ROCS), and pharmacophore modelling (Phase) – were evaluated for their ability to reproduce experimentally determined binding modes of 25 PDE4 inhibitors, identified by X-ray crystallography. Molecular docking was able to provide a good approximation (RMSD less than 2 Å) in 59% of cases, when considering the top binding pose. The pairwise comparisons, using molecular shape similarity, gave good matches in 42% of cases. Pharmacophore models were unable to predict good binding modes for a series of PDE4 inhibitors.


References


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