Discovery of Wild-Type and Y181C Mutant Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors Using Virtual Screening with Multiple Protein Structures

To discover non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that are effective against both wild-type (WT) virus and variants that encode the clinically troublesome Tyr181Cys (Y181C) RT mutation, virtual screening by docking was carried out using three RT structures and more than 2 million commercially available compounds. Two of the structures are for WT-virus with different conformations of Tyr181, while the third structure incorporates the Y181C modification. Eventually nine compounds were purchased and assayed. Three of the compounds show low-micromolar antiviral activity toward either or both the wild-type and Y181C HIV-1 strains. The study illustrates a viable protocol to seek anti-HIV agents with enhanced resistance profiles.

[1]  N. Yamamoto,et al.  Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay. , 1985, Science.

[2]  S. Sigurdsson,et al.  Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. , 2002, European journal of biochemistry.

[3]  X. Zou,et al.  Ensemble docking of multiple protein structures: Considering protein structural variations in molecular docking , 2006, Proteins.

[4]  D. Richman,et al.  Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[5]  William L. Jorgensen,et al.  Search for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase Using Chemical Similarity, Molecular Docking, and MM-GB/SA Scoring , 2007, J. Chem. Inf. Model..

[6]  J. Proudfoot,et al.  The evolution of synthetic oral drug properties. , 2005, Bioorganic & medicinal chemistry letters.

[7]  H. Carlson.  Protein flexibility and drug design: how to hit a moving target. , 2002, Current opinion in chemical biology.

[8]  Brian K. Shoichet,et al.  ZINC - A Free Database of Commercially Available Compounds for Virtual Screening , 2005, J. Chem. Inf. Model..

[9]  Christophe Meyer,et al.  Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains. , 2005, Journal of medicinal chemistry.

[10]  William L. Jorgensen,et al.  Gas‐phase and liquid‐state properties of esters, nitriles, and nitro compounds with the OPLS‐AA force field , 2001, J. Comput. Chem..

[11]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[12]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. , 2001, Bioorganic & medicinal chemistry letters.

[13]  T. Steitz,et al.  Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  W. L. Jorgensen,et al.  Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids , 1996 .

[15]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[16]  Kallings Lo,et al.  The first postmodern pandemic: 25 years of HIV/ AIDS. , 2008 .

[17]  Julian Tirado-Rives,et al.  Structural and energetic analyses of the effects of the K103N mutation of HIV-1 reverse transcriptase on efavirenz analogues. , 2004, Journal of medicinal chemistry.

[18]  Hege S. Beard,et al.  Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. , 2004, Journal of medicinal chemistry.

[19]  D. Richman,et al.  Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives. , 1988, The Journal of biological chemistry.

[20]  K A Johnson,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors , 1995, Science.

[21]  William L Jorgensen,et al.  From docking false-positive to active anti-HIV agent. , 2007, Journal of medicinal chemistry.

[22]  D. Stuart,et al.  3'-Azido-3'-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D I Stuart,et al.  Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors. , 2001, Journal of molecular biology.

[24]  D I Stuart,et al.  Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives. , 1998, Biochemistry.