3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

MODELING STUDIES. ON RESISTANCE USING STRUCTURAL DATA ON HIV-l PROTEASE – INHIBITOR COMPLEXES.

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:7 (abstract no. 6)

B. Govinda Rao, Eunice E. Kim, Joshua Boger, Mark A. Murcko, and Manuel A. Navia
Vertex Pharmaceuticals Incorporated., 40 Allston Street, Cambridge, MA 02139

Although HIV-1 protease inhibitors should be less susceptible to the development of resistance by mutation than the RT inhibitors for various reasons, escape mutants have been observed on serial passage of virus challenged by HIV-l protease inhibitors. It would be useful, therefore, to develop modeling approaches which might address susceptibility to resistance in order to guide the design of newinhibitors. We have considered two such approaches, based on how well an inhibitor stays within the envelope of the enzyme's interactions with its substrates and based on an inhibitor's proximity to enzyme side chains. These approaches were applied to compare three highly-potent HIV-1 protease inhibitors: (1) Ro 31-8959 (developed at Roche), (2) L-735,524 (developed at Merck) and (3) VB-ll,328 (developed at Vertex). X-ray crystal structural data of these inhibitors complexed with HIV-1 protease were used in all modeling analyses. The models of substrates used in the analysis were built by standard modeling methods. In this presentation, we will describe the details of these modeling methods and the results obtained by analysis of three mutants: I47V, I50V and I84V. These mutants were chosen because: (1) these residues are in the middle of the active site and are in direct contact with all the three inhibitors; (2) the changes are minimal and appropriate for testing these methods, which use static coordinates of the enzyme-inhibitor complexes; and (3) experimental K_i changes of some of these mutants are available for comparison. The results are displayed graphically to provide visual summary of possible susceptibility of the enzyme's active site residues to mutation in the presence of an inhibitor.

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1994-08-02
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