Kim EE, Rao BG, Deininger DD, Baker CT, Dwyer MD, Navia MA, Thomson JA, Tung RD; International Conference on AIDS.
Int Conf AIDS. 1994 Aug 7-12; 10: 7 (abstract no. 319A).
Vertex Pharmaceuticals, Incorporated, Cambridge, MA 02139.
We have solved the X-ray crystal structures of HIV-1 protease in complex with the clinically relevant inhibitors Ro 31-8959 (Roche), L-735,524 (Merck) and VX-478 (Vertex). VX-478 is representative of a novel compound class that is extraordinarily potent in vitro, orally available in vivo, and synthetically accessible. VX-478 evolved through the use of structure-based drug design, and is currently in advanced pre-clinical development. Crystals of the VX-478 complex diffract to 1.9 A resolution in space group P6(1), with unit cell lengths a = b = 63.5 A and c = 83.8 A. An initial refinement of the structure of the complex yields an R-factor of 19.4%. All three inhibitor complexes crystallize isomorphously, facilitating a direct comparison of the structures. This allows us to rationalize the observed differences in relative inhibitory potency in light of the different patterns of enzyme interaction seen with the enzyme. We have, in turn, exploited these unique structural insights to better understand and anticipate the possible development of resistance by the virus to these compounds, and to design effective second generation inhibitors in response.
Publication Types:
Keywords:
- Drug Design
- HIV Protease
- HIV Protease Inhibitors
- In Vitro
- Saquinavir
Other ID:
UI: 102211281
From Meeting Abstracts