Volume 3 Supplement 1

6th German Conference on Chemoinformatics, GCC 2010

Open Access

HYDEing the false positives – scoring for lead optimization

Journal of Cheminformatics20113(Suppl 1):P29

https://doi.org/10.1186/1758-2946-3-S1-P29

Published: 19 April 2011

It is highly desirable to have a scoring function that provides guidance for the design of compounds with optimized bioactivity. HYDE [1] is such a scoring function, considering the essential interactions in protein-ligand complexes. HYDE describes consistently hydrogen bonds, the hydrophobic effect and desolvation. Its basic principle is a well balanced assessment of the energetics of desolvation. Compared to most other scoring functions HYDE is not calibrated on affinity data, we use octanol/water partition data of small molecules for calibration. Only three major factors are taken into consideration: (a) local hydrophobicity, (b) solvent accessible surface, and (c) contact surface area. Based on these, energetically favorable and unfavorable contributions to the binding affinity can be assessed on an atomic level.

Atomic contributions can be visualized, which turns out to be particularly helpful in a lead-optimization setup. One may immediately identify energetically unfavorable arrangements, like a polar group without a counter-part in an otherwise hydrophobic pocket or two hydrogen bond acceptors facing each other. Medicinal chemists will immediately have ideas how to alter a given structure in order to gain activity.

It is demonstrated that HYDE is able to distinguish between strong binders, weak binders, and non-binders considering several p38 MAP kinase inhibitors [2]. In a congeneric series of thrombin inhibitors [3] it is shown that HYDE is able to score and rank single atom exchanges correctly.

Authors’ Affiliations

(1)
University of Hamburg, Center for Bioinformatics
(2)
Bayer CropScience, Industriepark Hoechst
(3)
BioSolveIT GmbH

References

  1. Lange G, Albrecht J, Klein R, Rarey M: Towards an Integrated Description of Hydrogen Bonding and Dehydration: Decreasing False Positives in Virtual Screening with the HYDE Scoring function. ChemMedChem. 2007, 3: 885-897.Google Scholar
  2. Regan J, et al: Pyrazole Urea-Based Inhibitors of p38 MAP Kinase: From Lead Compound to Clinical Candidate. J Med Chem. 2002, 45: 2994-3008. 10.1021/jm020057r.View ArticleGoogle Scholar
  3. Baum B, Mohamed M, Zayed M, Gerlach C, Heine A, Hangauer D, Klebe G: More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of Thrombin. J Med Chem. 2009, 390: 56-69.Google Scholar

Copyright

© Schneider et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.