Does a Diol Cyclic Urea Inhibitor of HIV-1 Protease Bind Tighter Than Its Corresponding Alcohol Form? A Study by Free Energy Perturbation and Continuum Electrostatics Calculations

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2001 Mar 29

PMID 11272701

Citations 2

Authors

L Wang

Y Duan

P Stouten

G V De Lucca

R M Klabe

P A Kollman

Affiliations

Soon will be listed here.

Abstract

The cyclic urea inhibitors of HIV-1 protease generally have two hydroxyl groups on the seven-membered ring. In this study, free energy perturbation and continuum electrostatic calculations were used to study the contributions of the two hydroxyl groups to the binding affinity and solubility of a cyclic urea inhibitor DMP323. The results indicated that the inhibitor with one hydroxyl group has better binding affinity and solubility than the inhibitor with two hydroxyl groups. Therefore, removal of one hydroxyl group from DMP323 may help to improve the properties of DMP323. This is also likely to be true for other cyclic urea inhibitors. The study also illustrated the difficulty in accurate modeling of the binding affinities of HIV-1 protease inhibitors, which involves many possible protonation states of the two catalytic aspartic acids in the active site of the enzyme.

Citing Articles

Identification of HIV inhibitors guided by free energy perturbation calculations.

Acevedo O, Ambrose Z, Flaherty P, Aamer H, Jain P, Sambasivarao S Curr Pharm Des. 2012; 18(9):1199-216.

PMID: 22316150 PMC: 3605731. DOI: 10.2174/138161212799436421.

Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV-1 protease inhibitors. A 3D-QSAR-CoMFA method for new antiviral drug design.

Avram S, Svab I, Bologa C, Flonta M J Cell Mol Med. 2003; 7(3):287-96.

PMID: 14594553 PMC: 6741422. DOI: 10.1111/j.1582-4934.2003.tb00229.x.

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