STRUCTURES OF TYR188LEU MUTANT AND WILD-TYPE HIV-1 REVERSE-TRANSCRIPTASE COMPLEXED WITH THE NONNUCLEOSIDE INHIBITOR HBY-097 - INHIBITOR FLEXIBILITY IS A USEFUL DESIGN FEATURE FOR REDUCING DRUG-RESISTANCE

The second generation Hoechst-Bayer non-nucleoside inhibitor, HBY 097 ylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-thione), is an extremely pot ent inhibitor of HIV-1 reverse transcriptase (RT) and of HIV-1 infecti on in cell culture. HEY 097 selects for unusual drug-resistance mutati ons in HIV-1 RT (e.g. Gly190Glu) when compared with other non-nucleosi de RT inhibitors (NNRTIs), such as nevirapine, alpha-APA and TIBO. We have determined the structure of HEY 097 complexed with wild-type HIV- 1 RT at 3.1 Angstrom resolution. The HIV-1 RT/KBY 097 structure reveal s an overall inhibitor geometry and binding mode differing significant ly from RT/NNRTI structures reported earlier, in that HEY 097 does not adopt the usual butterfly-like shape. We have determined the structur e of the Tyr188Leu HIV-1 RT drug-resistant mutant in complex with HEY 097 at 3.3 Angstrom resolution. HEY 097 binds to the mutant RT in a ma nner similar to that seen in the wild-type RT/HBY 097 complex, althoug h there are some repositioning and conformational alterations of the i nhibitor. Conformational changes of the structural elements forming th e inhibitor-binding pocket, including the orientation of some side-cha ins, are observed. Reduction in the size of the 188 side-chain and rep ositioning of the Phe227 side-chain increases the volume of the bindin g cavity in the Tyr188Leu HIV-1 RT/HBY 097 complex. Loss of important protein-inhibitor interactions may account for the reduced potency of HEY 097 against the Tyr188Leu HIV-1 RT mutant. The loss of binding ene rgy may be partially offset by additional contacts resulting from conf ormational changes of the inhibitor and nearby amino acid residues. Th is would suggest that inhibitor flexibility can help to minimize drug resistance. (C) 1998 Academic Press.