A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design.

Protein Sci. 1995 Sep;4(9):1881-903. Unique Identifier : AIDSLINE MED/96100655
Wallqvist A; Jernigan RL; Covell DG; Frederick Cancer Research and Development Center, National Cancer; Institute, Frederick, Maryland 21702, USA.

Abstract: The interface between protein receptor-ligand complexes has been studied with respect to their binary interatomic interactions. Crystal structure data have been used to catalogue surfaces buried by atoms from each member of a bound complex and determine a statistical preference for pairs of amino-acid atoms. A simple free energy model of the receptor-ligand system is constructed from these atom-atom preferences and used to assess the energetic importance of interfacial interactions. The free energy approximation of binding strength in this model has a reliability of about +/- 1.5 kcal/mol, despite limited knowledge of the unbound states. The main utility of such a scheme lies in the identification of important stabilizing atomic interactions across the receptor-ligand interface. Thus, apart from an overall hydrophobic attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci 3:717-729), a rich variety of specific interactions is observed. An analysis of 10 HIV-1 protease inhibitor complexes is presented that reveals a common binding motif comprised of energetically important contacts with a rather limited set of atoms. Design improvements to existing HIV-1 protease inhibitors are explored based on a detailed analysis of this binding motif.

Keywords: Alcohols/CHEMISTRY Binding Sites Chemistry, Physical *Drug Design Electrochemistry Hydrogen Bonding HIV Protease/CHEMISTRY/*METABOLISM HIV Protease Inhibitors/*CHEMISTRY/*METABOLISM HIV-1/*ENZYMOLOGY Models, Chemical Models, Molecular Protein Binding Sulfhydryl Compounds/CHEMISTRY Support, U.S. Gov't, P.H.S. Thermodynamics JOURNAL ARTICLE
960430
M9640809

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, Gill Foundation, the National Library of Medicine, Quest Diagnostics, Roche and Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 1996. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1996. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .