scholarly journals Comparative Binding Energy (COMBINE) Analysis for Understanding the Binding Determinants of Type II Dehydroquinase Inhibitors

ChemMedChem ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. 740-747 ◽  
Author(s):  
Antonio Peón ◽  
Claire Coderch ◽  
Federico Gago ◽  
Concepción González-Bello
Keyword(s):  
Binding Energy ◽  
Combine Analysis ◽  
Type Ii ◽  
Comparative Binding ◽  
Type Ii Dehydroquinase ◽  
Binding Determinants

Comparative Binding Energy (COMBINE) Analysis of Influenza Neuraminidase−Inhibitor Complexes

2001 ◽  
Vol 44 (6) ◽  
pp. 961-971 ◽  
Author(s):  
Ting Wang ◽  
Rebecca C. Wade
Keyword(s):  
Binding Energy ◽  
Neuraminidase Inhibitor ◽  
Combine Analysis ◽  
Comparative Binding

scholarly journals Prediction of Drug-Target Binding Kinetics for Flexible Proteins by Comparative Binding Energy Analysis

2021 ◽  
Author(s):  
Ariane Nunes Alves ◽  
Fabian Ormersbach ◽  
Rebecca Wade
Keyword(s):  
Binding Energy ◽  
Crystal Structures ◽  
Protein Complex ◽  
Protein Complexes ◽  
Combine Analysis ◽  
Least Squares Regression ◽  
Ligand Complex ◽  
Kinetic Rates ◽  
Multiple Structures ◽  
Comparative Binding

<div>There is growing consensus that the optimization of the kinetic parameters for drug-protein binding leads to improved drug efficacy. Therefore, computational methods have been developed to predict kinetic rates and to derive quantitative structure-kinetic relationships (QSKRs). Many of these methods are based on crystal structures of ligand-protein complexes. However, a drawback is that each protein-ligand complex is usually treated as having a single structure. Here, we present a modification of COMparative BINding Energy (COMBINE) analysis, which uses the structures of protein-</div><div>ligand complexes to predict binding parameters. We introduce the option to use multiple structures to describe each ligand-protein complex into COMBINE analysis and</div><div>apply this to study the effects of protein flexibility on the derivation of dissociation rate constants (k<sub>off</sub>) for inhibitors of p38 mitogen-activated protein (MAP) kinase, which has a flexible binding site. Multiple structures were obtained for each ligand-protein complex by performing docking to an ensemble of protein configurations obtained from molecular dynamics simulations. Coefficients to scale ligand-protein interaction energies determined from energy-minimized structures of ligand-protein complexes were obtained by partial least squares regression and allowed the computation of k<sub>off</sub> values. The QSKR model obtained using single, energy minimized crystal structures for each ligand-protein complex had a higher predictive power than the QSKR model obtained with multiple structures from ensemble docking. However, the incorporation of protein-ligand flexibility helped to highlight additional ligand-protein interactions that lead to longer residence times, like interactions with residues Arg67 and Asp168, which are close to the ligand in many crystal structures, showing that COMBINE analysis is a promising method to design leads with improved kinetic rates for flexible proteins.</div>

scholarly journals Prediction of Drug-Target Binding Kinetics for Flexible Proteins by Comparative Binding Energy Analysis

2021 ◽  
Author(s):  
Ariane Nunes Alves ◽  
Fabian Ormersbach ◽  
Rebecca Wade
Keyword(s):  
Binding Energy ◽  
Crystal Structures ◽  
Protein Complex ◽  
Protein Complexes ◽  
Combine Analysis ◽  
Binding Kinetics ◽  
Least Squares Regression ◽  
Ligand Complex ◽  
Multiple Structures ◽  
Comparative Binding

<div>There is growing consensus that the optimization of the kinetic parameters for drug-protein binding leads to improved drug efficacy. Therefore, computational methods have been developed to predict kinetic rates and to derive quantitative structure-kinetic relationships (QSKRs). Many of these methods are based on crystal structures of ligand-protein complexes. However, a drawback is that each protein-ligand complex is usually treated as having a single structure. Here, we present a modification of COMparative BINding Energy (COMBINE) analysis, which uses the structures of protein-</div><div>ligand complexes to predict binding parameters. We introduce the option to use multiple structures to describe each ligand-protein complex into COMBINE analysis and</div><div>apply this to study the effects of protein flexibility on the derivation of dissociation rate constants (k<sub>off</sub>) for inhibitors of p38 mitogen-activated protein (MAP) kinase, which has a flexible binding site. Multiple structures were obtained for each ligand-protein complex by performing docking to an ensemble of protein configurations obtained from molecular dynamics simulations. Coefficients to scale ligand-protein interaction energies determined from energy-minimized structures of ligand-protein complexes were obtained by partial least squares regression and allowed the computation of k<sub>off</sub> values. The QSKR model obtained using single, energy minimized crystal structures for each ligand-protein complex had a higher predictive power than the QSKR model obtained with multiple structures from ensemble docking. However, the incorporation of protein-ligand flexibility helped to highlight additional ligand-protein interactions that lead to longer residence times, like interactions with residues Arg67 and Asp168, which are close to the ligand in many crystal structures. These results show that COMBINE analysis is a promising method to guide the design of compounds that bind to flexible proteins with improved binding kinetics. </div>

scholarly journals Prediction of Drug-Target Binding Kinetics for Flexible Proteins by Comparative Binding Energy Analysis

2021 ◽  
Author(s):  
Ariane Nunes Alves ◽  
Fabian Ormersbach ◽  
Rebecca Wade
Keyword(s):  
Binding Energy ◽  
Crystal Structures ◽  
Protein Complex ◽  
Protein Complexes ◽  
Combine Analysis ◽  
Least Squares Regression ◽  
Ligand Complex ◽  
Kinetic Rates ◽  
Multiple Structures ◽  
Comparative Binding

<div>There is growing consensus that the optimization of the kinetic parameters for drug-protein binding leads to improved drug efficacy. Therefore, computational methods have been developed to predict kinetic rates and to derive quantitative structure-kinetic relationships (QSKRs). Many of these methods are based on crystal structures of ligand-protein complexes. However, a drawback is that each protein-ligand complex is usually treated as having a single structure. Here, we present a modification of COMparative BINding Energy (COMBINE) analysis, which uses the structures of protein-</div><div>ligand complexes to predict binding parameters. We introduce the option to use multiple structures to describe each ligand-protein complex into COMBINE analysis and</div><div>apply this to study the effects of protein flexibility on the derivation of dissociation rate constants (k<sub>off</sub>) for inhibitors of p38 mitogen-activated protein (MAP) kinase, which has a flexible binding site. Multiple structures were obtained for each ligand-protein complex by performing docking to an ensemble of protein configurations obtained from molecular dynamics simulations. Coefficients to scale ligand-protein interaction energies determined from energy-minimized structures of ligand-protein complexes were obtained by partial least squares regression and allowed the computation of k<sub>off</sub> values. The QSKR model obtained using single, energy minimized crystal structures for each ligand-protein complex had a higher predictive power than the QSKR model obtained with multiple structures from ensemble docking. However, the incorporation of protein-ligand flexibility helped to highlight additional ligand-protein interactions that lead to longer residence times, like interactions with residues Arg67 and Asp168, which are close to the ligand in many crystal structures, showing that COMBINE analysis is a promising method to design leads with improved kinetic rates for flexible proteins.</div>

gCOMBINE: A graphical user interface to perform structure-based comparative binding energy (COMBINE) analysis on a set of ligand-receptor complexes

2009 ◽  
Vol 78 (1) ◽  
pp. 162-172 ◽  
Author(s):  
Rubén Gil-Redondo ◽  
Javier Klett ◽  
Federico Gago ◽  
Antonio Morreale
Keyword(s):  
User Interface ◽  
Binding Energy ◽  
Graphical User Interface ◽  
Combine Analysis ◽  
Receptor Complexes ◽  
Comparative Binding

Comparative Binding Energy (COMBINE) Analysis Supports a Proposal for the Binding Mode of Epothilones to β-Tubulin

ChemMedChem ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. 836-843 ◽  
Author(s):  
Claire Coderch ◽  
Javier Klett ◽  
Antonio Morreale ◽  
J. Fernando Díaz ◽  
Federico Gago
Keyword(s):  
Binding Energy ◽  
Binding Mode ◽  
Combine Analysis ◽  
Comparative Binding ◽  
Β Tubulin
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