Rapid and Accurate Prediction of Binding Free Energies for Saquinavir-Bound HIV-1 Proteases

Stoica, Ileana; Sadiq, S. Kashif; Coveney, Peter V.

doi:10.1021/ja0779250

Cited by 143 publications

(190 citation statements)

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“…The LPV and RTV systems exhibited excellent peak correlation coefficients (k) of 0.84 and 0.93, respectively. The results are encouraging and they build on our earlier work (Stoica et al 2008). …”

Section: Drug Resistance In Hiv-1 Proteases and Reverse Transcriptasessupporting

confidence: 74%

“…We have previously investigated the applicability of binding free-energy methods in fully atomistic molecular simulations as a way of ranking drugresistant mutations of the inhibitor saquinavir (SQV; Stoica et al 2008). These used the molecular mechanics Poisson-Boltzmann surface area (MMPBSA; with the inclusion of configurational entropies from normal mode analysis (Brooks et al 1995) and gave excellent correlation to experimental values (Maschera et al 1996;Ermolieff et al 1997).…”

Section: Drug Resistance In Hiv-1 Proteases and Reverse Transcriptasesmentioning

confidence: 99%

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Real science at the petascale

Saksena

Boghosian

Fazendeiro

et al. 2009

Phil. Trans. R. Soc. A.

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We describe computational science research that uses petascale resources to achieve scientific results at unprecedented scales and resolution. The applications span a wide range of domains, from investigation of fundamental problems in turbulence through computational materials science research to biomedical applications at the forefront of HIV/AIDS research and cerebrovascular haemodynamics. This work was mainly performed on the US TeraGrid 'petascale' resource, Ranger, at Texas Advanced Computing Center, in the first half of 2008 when it was the largest computing system in the world available for open scientific research. We have sought to use this petascale supercomputer optimally across application domains and scales, exploiting the excellent parallel scaling performance found on up to at least 32 768 cores for certain of our codes in the so-called 'capability computing' category as well as highthroughput intermediate-scale jobs for ensemble simulations in the 32-512 core range. Furthermore, this activity provides evidence that conventional parallel programming with MPI should be successful at the petascale in the short to medium term. We also report on the parallel performance of some of our codes on up to 65 636 cores on the IBM Blue Gene/P system at the Argonne Leadership Computing Facility, which has recently been named the fastest supercomputer in the world for open science.

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Section: Drug Resistance In Hiv-1 Proteases and Reverse Transcriptasessupporting

confidence: 74%

Section: Drug Resistance In Hiv-1 Proteases and Reverse Transcriptasesmentioning

confidence: 99%

Real science at the petascale

Saksena

Boghosian

Fazendeiro

et al. 2009

Phil. Trans. R. Soc. A.

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“…Previously reported studies suggest longer MD trajectories may be required for the reliability of MM-PBSA/MM-GBSA energy estimates [40]. Thus, we performed 10 ns of unrestrained dynamics for each protein/NNIs complex to sample adequate conformational space for energy calculation.…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Insight into ligand selectivity in HCV NS5B polymerase: molecular dynamics simulations, free energy decomposition and docking

Froeyen

Herdewijn

2009

J Mol Model

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Modeling studies were performed on HCV NS5B Polymerase in an effort to design new inhibitors. The binding models of five different scaffold inhibitors were investigated and compared by using molecular dynamics simulations, free energy calculation and decomposition. Our results show Tyr448 plays the most critical role in the binding of most inhibitors. In addition, favorable contributions of residues Pro197, Arg200, Cys366, Met414 and Tyr448 in a deep hydrophobic pocket prove to be important for the selectivity of inhibitors. Furthermore, an optimized docking protocol was presented based on cross-docking the five inhibitors in the palm binding site of this enzyme using the Autodock program. This protocol was used later to virtually screen NCI and Maybridge diversity set libraries. The binding site was profiled via the statistics and analysis of the hydrogen bond networks formed between the receptor and the top-ranked diversity set compounds. Based on our detailed binding site analysis two useful rules were proposed to guide the selection of promising hits.Response to Reviewers: Question1: It is a pity that nothing in detail is discussed about found structures resulting from the virtual screening. Did the authors find new promising ligands with high (higher than the template ligands?) affinity and are they structurally diverse or similar to the used ones?Answer: We have found some promising compounds after the virtual screening. They are structurally diverse. Most of them form hydrogen bonds with the critical residues such as Tyr448 and have strong hydrophobic interaction with the residues in the deep hydrophobic pocket mentioned in our article. These compounds are under biological test.Question2: Additionally to figure 5 at least one figure should be added, showing the amino acid residues of the active site with the discussed most important interactions with one (the best?) ligand. This would considerably help to understand the discussion without looking in the original pdb-files. AbstractModeling studies were performed on HCV NS5B Polymerase in an effort to design new inhibitors. The binding models of five different scaffold inhibitors were investigated and compared by using molecular dynamics simulations, free energy calculation and decomposition. Our results show Tyr448 plays the most critical role in the binding of most inhibitors. In addition, favorable contributions of residues Pro197, Arg200, Cys366, Met414 and Tyr448 in a deep hydrophobic pocket prove to be important for the selectivity of inhibitors.Furthermore, an optimized docking protocol was presented based on cross-docking the five inhibitors in the palm binding site of this enzyme using the Autodock program. This protocol was used later to virtually screen NCI and Maybridge diversity set libraries. The binding site was profiled via the statistics and analysis of the hydrogen bond networks formed between the receptor and the top-ranked diversity set compounds. Based on our detailed binding site analysis two useful rules were proposed to ...

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“…The latter method is interesting because it is composed of physically well-defined terms and contains no adjustable parameters. It has been shown to be useful to estimate binding affinities, 16,17,18,19 although it sometimes fails. 20,21 A problem with this method has been the high statistical uncertainty of the estimates.…”

mentioning

confidence: 99%

Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA

Genheden

Nilsson

Ryde

2011

J. Chem. Inf. Model.

167

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We present free energy estimates of nine 3-amidinobenzyl-1H-indole-2-carboxamide inhibitors of factor Xa. Using alchemical thermodynamic integration (TI) calculations, we estimate the difference in binding free energies with high accuracy and precision, except for mutations involving one of the amidinobenzyl rings. Crystal studies show that the inhibitors may bind in two distinct conformations and using TI, we show that the two conformations give a similar binding affinity. Furthermore we show that we can reduce the computational demand, while still retaining a high accuracy and precision, by using fewer integration points and shorter protein-ligand simulations. Finally, we have compared the TI results to those obtained with the simpler MM/GBSA method (molecular-mechanics with generalised Born surface-area solvation). MM/GBSA gives better results for the mutations that involve a change of net charge, but if a precision similar to that of the TI method is required, the MM/GBSA method is actually slightly more expensive. Thus, we have shown that TI could be a valuable tool in drug design.2 Introduction Myocardial infarction, pulmonary embolism, and stroke are among the leading causes of death in the industrialised parts of the world. They are triggered by undesirable clot formation within blood vessels. The clot formation is initiated by an intricate series of enzymatic reactions that eventually generate fibrin.

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Rapid and Accurate Prediction of Binding Free Energies for Saquinavir-Bound HIV-1 Proteases

Cited by 143 publications

References 57 publications

Real science at the petascale

Real science at the petascale

Insight into ligand selectivity in HCV NS5B polymerase: molecular dynamics simulations, free energy decomposition and docking

Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA

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