Docking Ligands into Flexible and Solvated Macromolecules. 2. Development and Application of F<scp>itted</scp> 1.5 to the Virtual Screening of Potential HCV Polymerase Inhibitors

Corbeil, Christopher R.; Englebienne, Pablo; Yannopoulos, Constantin G.; Chan, Laval; Das, Sanjoy K.; Bilimoria, Darius; L’Heureux, Lucille; Moitessier, Nicolas

doi:10.1021/ci700398h

Cited by 56 publications

(58 citation statements)

References 38 publications

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“…As can be seen, 40% of the actives were both recovered in the top 5% of ranked NCI and HitFinder diversity set. Overall, a state-of-the-art virtual screening tool rarely extracts 100% of the actives in the top 10% and even more rarely in the top 5%; 50-60% in the top 5% is more commonly observed with the best programs [47]. In addition, considering that all the actives are low micromolar lead compounds and new actives is possible existing in the decoy set, the enrichment achieved by this docking protocol is reasonable and promising.…”

Section: Virtual Screening Against Diversity Setsmentioning

confidence: 92%

“…It is common practice to see a library of drug-like molecules with known actives and use the enrichment factor obtained to evaluate the accuracy of the docking and scoring functions of the software [47]. Figure 6 shows the percentage of the number of known inhibitors retrieved when increasing the fraction of the ranked list.…”

Section: Virtual Screening Against Diversity Setsmentioning

confidence: 99%

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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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Section: Virtual Screening Against Diversity Setsmentioning

confidence: 92%

Section: Virtual Screening Against Diversity Setsmentioning

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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“…Thus, the inclusion of the interaction sites oriented the docking toward better solutions and, as a result, afforded a 10% increase in accuracy over FITTED 1.0 and a significant decrease in required CPU time. 36 FITTED was then used in the screening of the Maybridge database against HCV polymerase and was successful in identifying two hits in the low micromolar range. 36 FITTED2.6.…”

Section: Introductionmentioning

confidence: 99%

Docking Ligands into Flexible and Solvated Macromolecules. 3. Impact of Input Ligand Conformation, Protein Flexibility, and Water Molecules on the Accuracy of Docking Programs

Corbeil

Moitessier

2009

J. Chem. Inf. Model.

Self Cite

106

130

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Several modifications and additions to Fitted1.5 led to the development of Fitted2.6. Among the novel implementations are a matching algorithm-enhanced genetic algorithm and a ring conformational search algorithm. With these various optimizations, we also hoped to remove the biases and to develop a docking program that would provide results (i.e., poses) as independent as possible to the input ligand and protein conformations and used parameters, although keeping the options to provide additional experimental information. These biases were investigated within Fitted2.6 along with FlexX, GOLD, Glide, and Surflex. The input ligand conformation was found to have a major impact on the program accuracy as drops as large as 10-50% were observed with all the programs but Fitted. This comparative study also demonstrates that the accuracy of Fitted is similar to that of other widely used programs. We have also demonstrated that protein flexibility, displaceable water molecules, and ring conformational search algorithms, three of the main Fitted features, significantly increased its accuracy. Finally, we also proposed potential modifications to the available programs to further improve their accuracy in binding mode prediction.

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“…Currently, virtual screening methods are being considered as promising approaches to accelerate drug discovery. [57][58][59] In the present study, we successfully identified a potent inhibitor of HCV NS5B by using a structure-based virtual screening of the Maybridge Screening Collection and the in vitro cell-based reporter assay. If more diverse potential drug candidates can be identified, then greater is the possibility of developing new therapies for inhibiting HCV.…”

Section: Discussionmentioning

confidence: 99%

EfficientIn SilicoAssay of Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase by Structure-Based Virtual Screening andIn VitroEvaluation

Lin

Huang

Tseng

et al. 2011

ASSAY and Drug Development Technologies

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To identify a new protective or therapeutic intervention for hepatitis C virus (HCV) infection, we performed efficient structure-based virtual screening to identify novel inhibitory agents for HCV. To this end, we selected NS5B, an RNA-dependent RNA polymerase (RdRp), as the target for the treatment of HCV infection. To decipher the dockable nature of various RdRp X-ray crystals, we docked the crystal ligand (inhibitor) to the crystal receptor (enzyme). The accuracy of regeneration of the crystal pose indicates the amenability of the RdRp binding pocket for structure-based virtual screening. We also utilized a consensus scoring scheme to reduce false positives, thereby ensuring efficient virtual screening. In this study, each molecule that ranked in the top 1% among all screening molecules gained 1 consensus point in a scoring function. Thus, after virtual screening of 57,177 chemicals from the Maybridge Screening collection, 14 molecules gained 8 points across 11 scoring functions. One of them, an isoxazole, showed significant dose-dependent inhibition of HCV RdRp activity and replication. In this study, we have developed a structure-based virtual screening method using HCV RdRp for efficient identification of novel inhibitors.

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Docking Ligands into Flexible and Solvated Macromolecules. 2. Development and Application of Fitted 1.5 to the Virtual Screening of Potential HCV Polymerase Inhibitors

Cited by 56 publications

References 38 publications

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

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

Docking Ligands into Flexible and Solvated Macromolecules. 3. Impact of Input Ligand Conformation, Protein Flexibility, and Water Molecules on the Accuracy of Docking Programs

EfficientIn SilicoAssay of Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase by Structure-Based Virtual Screening andIn VitroEvaluation

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