A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.

Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP "chlorine scan" was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC 50 ) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 10-20 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEPguided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative.

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[reaction: see text] A new synthetic procedure for aminohalogenation of olefins has been developed for the preparation of vicinal haloamine derivatives in high yields by using Cu, Mn, or V catalysts with p-toluenesulfonamide (TsNH(2)) and N-bromosuccinimide (NBS) as nitrogen and bromine sources, respectively. Unprecedented regio- and stereoselectivity (anti:syn > 99:1) toward the aminohalogenation process is shown for olefinic substrates as well as transition metal catalysts.

Non-nucleoside inhibitors of HIV reverse transcriptase (NNRTIs) 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 analog 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC50 values of 2 and 10 nM. 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 towards 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.

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Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with the assistance of free energy perturbation (FEP) calculations to predict relative free energies of binding. Extension of azole-containing inhibitors into an 'eastern' channel between Phe227 and Pro236 has led to the discovery of potent and structurally novel derivatives.Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are an important component of highly active anti-retroviral therapy (HAART) for the treatment of HIV infection. 1 NNRTIs disrupt the activity of HIV-RT via binding to an allosteric pocket in the vicinity of the polymerase active site. [2][3][4] However, the therapeutic effectiveness of NNRTIs is challenged by rapid emergence of drug-resistant, variant strains of the virus. 5 Mutations such as V106A, Y181C, and K103N occur in the NNRTI binding pocket. While the search for an effective vaccine continues, the need for new antiretroviral drugs with improved pharmacological properties and resistance profiles is apparent.Recent reports have described the discovery and free energy perturbation (FEP)-guided optimization of an U-5Het-NH-Ar scaffold, where U is an unsaturated hydrophobic group, and 5Het is an azole. 6,7 Though potent NNRTIs were identified with EC 50 values as low as 10-20 nM, search for novel NNRTIs that provide activity against a broader spectrum of variants continues. In particular, we have sought to reduce the dependence of the NNRTI binding on the interaction between the U group and Tyr181 by extending the Ar group into the distal region of the binding site, which is lined by Val106, Glu224, Pro225, Pro226, Phe227 and Pro236. The present report summarizes FEP-guided results for these 'eastern extensions' in the oxazole and oxadiazole series.The syntheses of oxadiazole 1 and oxazole 3 derivatives were performed as shown in Schemes 1 and 2. 6 The isothiocyanates 2 required for the synthesis of oxazole derivatives 3 were prepared from substituted benzyl alcohols, phenols, or halonitrobenzenes. 8 ,9 As illustrated for 1e, extended oxadiazole derivatives were synthesized by Cu-catalyzed coupling of 2-aminooxadiazole 4 with aryl iodides, e.g., 5. 10,11 4 was synthesized from 2-(2,6-dichlorophenyl) © 2010 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript acetohydrazide and cyanogen bromide. 12,13 Coupling partner 5 was prepared by alkylation of 4-iodo-benzyl alcohol with the requisite bromomethyl-pyridine.Activities ...

In order 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 anti-viral activity towards 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.