Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO)

Weiser, Jörg; Shenkin, Peter S.; Still, W. Clark

doi:10.1002/(sici)1096-987x(19990130)20:2<217::aid-jcc4>3.0.co;2-a

Cited by 1,067 publications

(872 citation statements)

References 28 publications

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“…Following the MM/GBSA approach as described, [16][17][18] the affinity of wild-type and mutated PDGFRAs toward imatinib (DG bind ) was calculated as the sum of the electrostatic, van der Waals, polar salvation, 19 nonpolar salvation 20 and entopic contributions. 21 …”

Section: Molecular Modelingmentioning

confidence: 99%

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

Dileo

Pricl

Tamborini

et al. 2010

Intl Journal of Cancer

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Beside the well known “in vivo” and “in vitro” Imatinib resistant D842V mutation in PDGFRA receptor, very few are the information concerning the “in vivo” Imatinib activity with respect to the other PDGFRA mutations for which only “in vitro” data are available. Two patients carrying PDGFRA mutations in exons 18 (involving residues DIMH842‐845) and 12 (V561D), respectively, were treated with Imatinib at a dose of 400 mg/day. According to Response Evaluation Criteria in Solid Tumors criteria, after a median treatment of 7 months both patients showed clinical partial response, and underwent surgery of the minimal residual disease. Tumor response was confirmed pathologically. In both patients, analyses of PDGFRA performed on pre‐ and/or post‐treatment material were compared to affinity data of the mutated receptor towards the inhibitor. Molecular modeling evidence was found to be consistent with sensitivity of mutated PDGFRA receptors to Imatinib. Thus, the “in vivo” evidence that these two mutations of PDGFRA are sensitive to Imatinib was confirmed by a multidimensional approach comprising “in silico” experiments that, in association to molecular and biochemical analyses, constitutes a powerful tool to predict Imatinib sensitivity, clinically beneficial in the treatment of these tumors with molecularly targeted therapies.

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Section: Molecular Modelingmentioning

confidence: 99%

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

Dileo

Pricl

Tamborini

et al. 2010

Intl Journal of Cancer

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“…The dielectric constant was set to 1 for the interior solute and 80 for the surrounding solvent. The LCPO method [27] was used to calculate the Solvent Accessible Surface Area (SASA) for the estimation of the nonpolar solvation free energy (ΔG np ) with =0.0072 kcal mol -1 Å -2 and =0.00 kcal mol -1 [28]. The polar contribution (ΔG GB ) of desolvation was computed using a modified GB model developed by Onufriev et al [29].…”

Section: Mm/gbsa Calculation and Free Energy Decompositionmentioning

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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“…This method allows us to carry out analyses of protein-DNA interactions easily by decomposition into free energy components including entropy and also into substructure interactions. So far, a majority of studies using the MM-PBSA approach have dealt with the stability of single biomolecules, 17,18 protein-ligand binding, [19][20][21] or protein-protein interactions. 22 A limited number of studies have been published on the protein-nucleic acid binding problem to the best of our knowledge.…”

Section: Introductionmentioning

confidence: 99%

Cooperativity and Specificity of Cys₂His₂ Zinc Finger Protein−DNA Interactions: A Molecular Dynamics Simulation Study

Lee

Seok

2010

J. Phys. Chem. B

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Cys 2 His 2 zinc finger proteins are one of the most frequently observed DNA-binding motifs in eukaryotes. They have been widely used as a framework for designing new DNA-binding proteins. In this work, the binding affinity and conformational change of the Zif268-DNA complex were successfully reproduced with MD simulations and MM-PBSA analysis. The following new discoveries on the zinc finger protein-DNA interactions were obtained by careful energy decomposition analysis. First, a dramatic increase in the binding affinity was observed when the third zinc finger is added, indicating a cooperative nature. This cooperativity is shown to be a consequence of the small but distinctive conformational change of DNA, which enables a tight fit of the protein into the major groove of DNA. Second, specificity of the amino acid-nucleotide recognitions observed in the crystal structure is explained as originating from the ability of specific side chains and bases to take the optimal geometries for favorable interactions between polar groups. The success of the current approach implies that similar methods could be further applied to the study of protein-DNA interactions involving longer polyfingers or different linkers between fingers to provide insights for design of novel zinc finger proteins.

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Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO)

Cited by 1,067 publications

References 28 publications

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

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

Cooperativity and Specificity of Cys₂His₂ Zinc Finger Protein−DNA Interactions: A Molecular Dynamics Simulation Study

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Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO)

Cited by 1,067 publications

References 28 publications

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

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

Cooperativity and Specificity of Cys2His2 Zinc Finger Protein−DNA Interactions: A Molecular Dynamics Simulation Study

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Cooperativity and Specificity of Cys₂His₂ Zinc Finger Protein−DNA Interactions: A Molecular Dynamics Simulation Study