613 Could Multiple Modes of Binding of a Potent NNRTI TMC125-R165335 Explain Its Potency Against Common Drug-resistant Mutants? K Das1, A D Clark1, P L Boyer2, D W Ludovici3, M-P de Béthune4, K Andries5, P Lewi*6, E Arnold1, S H Hughes2, B L De Corte3, R W Kavash3, M J Kukla3, R Pauwels4, M de Jonge6, F Daeyaert6, L Koymans6, M Vinkers6, J Heeres6, P A Janssen6 1Ctr for Advanced Biotechnology and Med and Rutgers Univ, Piscataway, NJ; 2Natl Inst of Hlth -NCI HIV Drug Resistance Prgm, Frederick, MD; 3Janssen Res Fndn, Springhouse, PA; 4Tibotec-Virco, Mechelen, Belgium; 5J&J PRD, Beerse, Belgium; and 6Ctr for Molecular Design, Vosselaar, Belgium
Background: A multidisciplinary effort has resulted in the development of several new series of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), including diaryltriazine (DATA) and dianilinopyrimidine (DAPY) compounds. A DAPY compound TMC125-R165335 was found to be highly potent against a broad range of clinically relevant HIV-1 variants, including those containing L100I, K103N, and Y181C mutations in RT.
Method: In a Phase I/II clinical trial treatment-naïve patients (pts) received 2 900 mg doses of TMC125-R165335 per day for one wk. The mean viral load (RNA copies/ml) decreased 1.9 log10- comparable to the viral load reduction achieved using a combination of 5 anti-AIDS drugs in a parallel arm of the trial.
Results: Throughout the drug development process, structures of HIV-1 RT complexed with key inhibitors were determined by X-ray crystallography. Molecular modeling was used to evaluate structural determinants of inhibitor potency and to guide further synthesis. Most of the DAPY and DATA compounds assume a "horseshoe" shape when they bind to HIV-1 RT. Surprisingly, a DATA compound containing a chloroindole ring binds in an alternate "seahorse" mode. Significant differences were observed also in the favored "horseshoe-like" mode of binding of DATA and DAPY compounds when the HIV-1 RT/NNRTI complex structures were compared.
Conclusions: Our structural and molecular modeling studies suggest that some of the most potent of these NNRTIs, including TMC125-R165335, can adopt multiple stable modes of binding to HIV-1 RT. Switching the conformations of NNRTIs from one mode of binding to another does not involve a significant energetic cost. A consequence of having several binding modes available for TMC125-R165335 is that a single drug molecule might be able to behave as a combination of drugs, corresponding to the various binding modes. NNRTI resistance mutations affect the size, shape, and/or chemical nature of the binding pocket; the NNRTIs could adopt different binding modes against different resistant RTs and thus remain effective.
