title: Efficient discovery of potent anti-HIV agents targeting the Tyr181Cys variant of HIV reverse transcriptase.
abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued with guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein-inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC(50) values of 2 and 10 nM, respectively. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 μM). The present report details the efficient, computationally driven evolution of 3 to novel NNRTIs with sub-10 nM potency toward both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States. william.jorgensen@yale.edu
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollini
authors.forename: Vinay V
authors.initials: VV
authors.lastname: Thakur
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domaoal
authors.forename: Krasimir A
authors.initials: KA
authors.lastname: Spasov
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000737:chemistry; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014227:Triazines / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011743:Pyrimidines; D014227:Triazines; D054303:HIV Reverse Transcriptase; C030986:pyrimidine