Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

Jorgensen, William L.; Bollini, Mariela; Thakur, Vinay V.; Domaoal, Robert A.; Spasov, Krasimir A.; Anderson, Karen S.

doi:10.1021/ja2058583

Cited by 61 publications

(51 citation statements)

References 43 publications

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“…21 Details of the calculations are described elsewhere. 22 Briefly, the OPLS-AA force field is used for the protein, OPLS/CM1A for the ligands, and TIP4P for water molecules. 23 For the FEP calculations, the unbound ligands and complexes were solvated in water caps with a 25 Å radius, amounting to ca.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

et al. 2015

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Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl–aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.

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Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

et al. 2015

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“…46 Such compounds were synthesized including 17 (EC 50 = 48 nM), and eventually the triazine 18 (1.7 nM). 46 FEP calculations made another important contribution in predicting that a cyclopropyl, isopropyl, or thiomethyl substituent in the triazine or pyrimidine ring would provide significant activity boosts, which indeed turned out to be five-fold over methoxy. Furthermore, as expected, the elaborated compounds did gain significant activity towards the Y181C–containing viral strain.…”

Section: Trouble With Y181cmentioning

confidence: 99%

Computer-aided discovery of anti-HIV agents

Jorgensen

2016

Bioorganic & Medicinal Chemistry

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A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.

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“…Structural preparation of the benzyloxazole ligands in complex with the HIV-RT receptor followed identical protocols as described elsewhere [8,27-30]. Briefly, the model system was built from the PDB ID: 1S9E file [31], using the MCPRO [17] and BOMB [1] software packages.…”

Section: Computational Detailsmentioning

confidence: 99%

Molecular dynamics and Monte Carlo simulations for protein–ligand binding and inhibitor design

Cole

Tirado‐Rives

Jorgensen

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Non-nucleoside inhibitors of HIV reverse transcriptase are an important component of treatment against HIV infection. Novel inhibitors are sought that increase potency against variants that contain the Tyr181Cys mutation. Methods Molecular dynamics based free energy perturbation simulations have been run to study factors that contribute to protein–ligand binding, and the results are compared with those from previous Monte Carlo based simulations and activity data. Results Predictions of protein–ligand binding modes are very consistent for the two simulation methods, which are attributed to the use of an enhanced sampling protocol. The Tyr181Cys binding pocket supports large, hydrophobic substituents, which is in good agreement with experiment. Conclusions Although some discrepancies exist between the results of the two simulation methods and experiment, free energy perturbation simulations can be used to rapidly test small molecules for gains in binding affinity. General significance Free energy perturbation methods show promise in providing fast, reliable and accurate data that can be used to complement experiment in lead optimization projects. This article is part of a Special Issue entitled “Recent developments of molecular dynamics”.

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Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

Cited by 61 publications

References 43 publications

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

Computer-aided discovery of anti-HIV agents

Molecular dynamics and Monte Carlo simulations for protein–ligand binding and inhibitor design

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