From Docking False-Positive to Active Anti-HIV Agent

Barreiro, Gabriela; Kim, Joseph T.; Guimarães, Cristiano Ruch Werneck; Bailey, Christopher M.; Domaoal, Robert A.; Wang, Ligong; Anderson, Karen S.; Jorgensen, William L.

doi:10.1021/jm070683u

Cited by 62 publications

(74 citation statements)

References 34 publications

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“…A set of small substituents was reintroduced in place of each hydrogen; scoring with the BOMB program and FEP results led to synthesis and assaying of several polychloro analogues with EC 50 values as low as 310 nM in an HIV-infected T-cell assay. 5 The present report documents the FEP-guided developments that have now led to analogues of 2 with potencies in the 10-20 nM range. The essentially exhaustive FEP-guided lead optimization can serve as a model for future applications.…”

Section: Introductionmentioning

confidence: 81%

Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations

et al. 2008

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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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Section: Introductionmentioning

confidence: 81%

Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations

et al. 2008

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“…Machicado and co-workers reported that prior to docking screening, the pre-selection of compounds was developed on the basis of volume and polarity characteristics [142], Barreiro and co-workers used a chemical similarity search [143,144], and Hu and co-workers discovered new Yersinia protein kinase A inhibitors by applying, prior to the docking studies, a machine-learning support vector machine model for obtaining a target-focused library beginning with a large chemical database [145].…”

Section: Other Docking-based Vs Methodsmentioning

confidence: 99%

“…Many successful VS results have been reported, and as suggested by Barreiro and co-workers, when the VS results seem to be second-rate, it is possible to use computational analyses to efficiently turn false positives into true active compounds [143,144].…”

Section: Conclusion and Future Trendsmentioning

confidence: 99%

Docking-Based Virtual Screening: Recent Developments

Tuccinardi

2009

CCHTS

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Virtual (database) screening (VS) of molecules promises to accelerate the discovery of new drugs and reduce costs by identifying molecules with high probabilities of binding to a target receptor. The large amount of available protein X-ray crystal structures, together with the development of more effective homology modelling techniques, has led recently to a steep increase in docking-based VS studies. This approach needs computational fitting of molecules into a receptor active site using advanced algorithms, followed by the scoring and ranking of these molecules to identify potential leads. In this review, the main published docking-based VS studies developed over the last eight years are investigated, and details are provided about the software used, the results achieved and the novel methods employed.

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“…Barreiro et al [48,101] docked a library of 70,000 commercially available compounds from the Maybridge catalog and 26 known NRRTIs into the HIV-1 RT binding site in order to identify potential leads. The docking program Glide 3.5, using its standard and extra-precision modes [102,103], narrowed down the search to the top 100 compounds which were postscored using an MM-GB/SA method.…”

Section: Hiv-1 Rtmentioning

confidence: 99%

“…FEP/MC guided optimization of a thiazole scaffold towards a low nM HIV-1 RT pyrimidine-based inhibitor [98][99][100]. FEP/MC guided optimization of an inactive oxadiazole scaffold towards a low nM HIV-1 RT inhibitor [48,70,101]. Transformation sequence used in the FEP simulations for the aryl 1-indanylketone-based compounds (2).…”

Section: Chemical Synthesismentioning

confidence: 99%

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Acevedo¹,

Ambrose²,

Flaherty³

et al. 2012

curr drug metab

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Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

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From Docking False-Positive to Active Anti-HIV Agent

Cited by 62 publications

References 34 publications

Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations

Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations

Docking-Based Virtual Screening: Recent Developments

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

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