ABSTRACT
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.
Subject(s)
Anti-HIV Agents/chemistry , Catechols/chemistry , Computer Simulation , Models, Molecular , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Catechols/chemical synthesis , Catechols/pharmacology , Ethers/chemical synthesis , Ethers/chemistry , Ethers/pharmacology , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , Humans , Molecular Structure , Protein Binding , Quantitative Structure-Activity Relationship , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Stereoisomerism , T-Lymphocytes/drug effects , T-Lymphocytes/virologyABSTRACT
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.
Subject(s)
Amino Acid Substitution , Anti-HIV Agents/pharmacology , Drug Discovery , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , HIV Reverse Transcriptase/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular Targeted Therapy , Nitriles/chemistry , Protein Conformation , Pyrimidines/chemistry , Structure-Activity Relationship , Thermodynamics , Triazines/chemistryABSTRACT
A protected cyclitol aglycon was tethered to an (N-arylsulfonyl)glucosamine donor by a methylene linker; the exclusively alpha-selective intramolecular glycosylation reaction was then initiated by electrophilic activation of the thioglycoside donor portion. Further transformations of the glycosylation product to give the M. tuberculosis detoxifier mycothiol and its oxidized congener, the disulfide mycothione, are detailed.
Subject(s)
Cysteine/chemical synthesis , Glycopeptides/chemical synthesis , Inositol/chemical synthesis , Catalysis , Cysteine/chemistry , Glucosamine/chemistry , Glycopeptides/chemistry , Glycosylation , Inositol/chemistry , Molecular Structure , Mycobacterium tuberculosis/chemistry , Nuclear Magnetic Resonance, Biomolecular , Stereoisomerism , Thioglycosides/chemical synthesis , Thioglycosides/chemistryABSTRACT
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.
Subject(s)
Azoles/pharmacology , HIV-1/enzymology , Reverse Transcriptase Inhibitors/pharmacology , Azoles/chemistry , Models, Molecular , Reverse Transcriptase Inhibitors/chemistryABSTRACT
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.
Subject(s)
Drug Design , Reverse Transcriptase Inhibitors/chemistry , Drug Evaluation, Preclinical , Models, Molecular , Reverse Transcriptase Inhibitors/pharmacologyABSTRACT
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 (EC50) 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. FEP-guided 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.
Subject(s)
Azoles/chemistry , Azoles/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Azoles/chemical synthesis , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/genetics , HIV-1/genetics , Models, Molecular , Monte Carlo Method , Mutation , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxazoles/chemical synthesis , Oxazoles/chemistry , Oxazoles/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , ThermodynamicsABSTRACT
Non-nucleoside inhibitors of HIV-1 reverse transcriptase are being pursued through synthesis and assaying for anti-viral activity. Following computational analyses, the focus has been on the motif Het-NH-Ph-U, where Het is an aromatic heterocycle and U is an unsaturated, hydrophobic group. Previous investigations with Het=2-thiazoyl and 2-pyrimidinyl are extended here to triazinyl derivatives. The result is several NNRTIs in the 2-20 nM range with negligible cytotoxicity and auspicious predicted pharmacological properties.
Subject(s)
Amines/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/pharmacology , Triazines/pharmacology , Amines/chemistry , Pyrimidines/chemistry , Triazines/chemistryABSTRACT
[reaction: see text] Commercial 1,2:5,6-di-O-isopropylidene-alpha-d-allofuranose was converted to a protected bicyclic octosyl acid thioglycoside donor by a 10-step sequence that features an intramolecular ester enolate alkylation. Glycosylation of N-benzoyladenine and methyl uridine-5-carboxylate followed by deprotection gave the respective nucleosides "octosyl adenine" and octosyl acid A.
Subject(s)
Nucleosides/chemical synthesis , Adenine/chemistry , Glycosylation , Molecular StructureABSTRACT
[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.
