Roles of Conformational and Positional Adaptability in Structure-Based Design of TMC125-R165335 (Etravirine) and Related Non-nucleoside Reverse Transcriptase Inhibitors That Are Highly Potent and Effective against Wild-Type and Drug-Resistant HIV-1 Variants

Kalyan Das, Arthur D. Clark, Paul J. Lewi, Jan Heeres, Marc R. De Jonge, Lucien M.H. Koymans, H. Maarten Vinkers, Frederik Daeyaert, Donald W. Ludovici, Michael J. Kukla, Bart De Corte, Robert W. Kavash, Chih Y. Ho, Hong Ye, Mark A. Lichtenstein, Koen Andries, Rudi Pauwels, Marie Pierre De Béthune, Paul L. Boyer, Patrick ClarkStephen H. Hughes, Paul A.J. Janssen, Eddy Arnold

Research output: Contribution to journalArticle

443 Scopus citations

Abstract

Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1) DAPY analogues can bind in at least two conformationally distinct modes; (2) within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3) the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket "jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.

Original languageEnglish (US)
Pages (from-to)2550-2560
Number of pages11
JournalJournal of medicinal chemistry
Volume47
Issue number10
DOIs
StatePublished - May 6 2004

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Roles of Conformational and Positional Adaptability in Structure-Based Design of TMC125-R165335 (Etravirine) and Related Non-nucleoside Reverse Transcriptase Inhibitors That Are Highly Potent and Effective against Wild-Type and Drug-Resistant HIV-1 Variants'. Together they form a unique fingerprint.

  • Cite this

    Das, K., Clark, A. D., Lewi, P. J., Heeres, J., De Jonge, M. R., Koymans, L. M. H., Vinkers, H. M., Daeyaert, F., Ludovici, D. W., Kukla, M. J., De Corte, B., Kavash, R. W., Ho, C. Y., Ye, H., Lichtenstein, M. A., Andries, K., Pauwels, R., De Béthune, M. P., Boyer, P. L., ... Arnold, E. (2004). Roles of Conformational and Positional Adaptability in Structure-Based Design of TMC125-R165335 (Etravirine) and Related Non-nucleoside Reverse Transcriptase Inhibitors That Are Highly Potent and Effective against Wild-Type and Drug-Resistant HIV-1 Variants. Journal of medicinal chemistry, 47(10), 2550-2560. https://doi.org/10.1021/jm030558s