Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)

Natesan, Senthil; Subramaniam, Rajesh; Bergeron, Charles; Baláž, Štefan

doi:10.1021/jm201217q

Cited by 33 publications

(27 citation statements)

References 66 publications

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“…Autodock was used for this work, after we compared several different docking programs for how well they were able to reproduce the position within the active site of analogues of ATP compared to that of the crystal structure. This work revealed that that the protonation state of inhibitors had a pronounced effect on docking, consistent with work by others [25]. From about 5000 compounds chosen in our initial screening of the NCI and ZINC libraries, about 20 purchasable compounds were assayed as described below.…”

Section: Pathway To Discovering a Family Of Inhibitors Of Efsupporting

confidence: 83%

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

Schein

Chen

et al. 2012

Toxins

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Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin’s basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.

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Section: Pathway To Discovering a Family Of Inhibitors Of Efsupporting

confidence: 83%

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

Schein

Chen

et al. 2012

Toxins

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“…Natesan et al developed the QM/MM-Linear Interaction Energy approach to account for multiple ligand tautomers and protomers. [44] They applied single-point B3LYP/6-31G*/AMBER level of theory to 66 inhibitors of MAPK-activated protein kinase. This protocol resulted in improving the correlation between calculated and experimental binding affinities (R 2 ) from 0.66 to 0.91.…”

Section: Combination Of Scoring With Quantum Mechanics Calculationsmentioning

confidence: 99%

“…While QM methods currently provide mostly auxiliary tools, mainly for rescoring of docked or MD-derived binding modes, their great potential of improving binding affinity prediction is exemplified in the studies discussed earlier. [44,59,60,96,97] The first first-principles-based function, [59] the derivation of which required no fitting to experimental data, may well be manifesting the beginning of a new era in docking research, where hardware and algorithm developments make it possible to apply first-principles theoretical treatment to affinity predictions. Free from approximations and simplifications associated with force-field, empirical, and knowledge-based scoring functions and implicit solvent rescoring methods, QM calculations offer opportunities for target-independent treatment of protein-ligand systems, including incorporation of polarizability and binding-associated ligand strain.…”

Section: Concluding Remarks On Trends and New Ideasmentioning

confidence: 99%

Improvements, trends, and new ideas in molecular docking: 2012–2013 in review

Yuriev

Holien

Ramsland

2015

J of Molecular Recognition

239

165

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Molecular docking is a computational method for predicting the placement of ligands in the binding sites of their receptor(s). In this review, we discuss the methodological developments that occurred in the docking field in 2012 and 2013, with a particular focus on the more difficult aspects of this computational discipline. The main challenges and therefore focal points for developments in docking, covered in this review, are receptor flexibility, solvation, scoring, and virtual screening. We specifically deal with such aspects of molecular docking and its applications as selection criteria for constructing receptor ensembles, target dependence of scoring functions, integration of higher-level theory into scoring, implicit and explicit handling of solvation in the binding process, and comparison and evaluation of docking and scoring methods.

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“…We prefer to use the Linear Response (LR) method in our quantum mechanics/molecular mechanics (QM/MM) modification [81-85] because of a favorable cost/performance ratio and the ability to cope with polarized H-bonds and electrostatic interactions, coordination bonds, and other interactions that cause problems when classical force fields are deployed. The procedure starts with best docked poses, which have the geometry and charges optimized by a QM/MM approach, and performs the conformational space mapping by a force-field based molecular dynamics (MD) of the hydrated complex.…”

Section: Introductionmentioning

confidence: 99%

“…The multispecies QM/MM-LR approach was applied to 66 benzothiophene and pyrrolopyridine inhibitors of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) [85]. The compounds form a complex network of up to five tautomers and seven ionization species (233 species altogether), and the binding site is available in one ionization/tautomer species only.…”

Section: Introductionmentioning

confidence: 99%

Rigorous Incorporation of Tautomers, Ionization Species, and Different Binding Modes into Ligand-Based and Receptor-Based 3D-QSAR Methods

Natesan¹,

Baláž²

2013

CPD

Self Cite

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Speciation of drug candidates and receptors caused by ionization, tautomerism, and/or covalent hydration complicates ligand- and receptor-based predictions of binding affinities by 3-dimensional structure-activity relationships (3D-QSAR). The speciation problem is exacerbated by tendency of tautomers to bind in multiple conformations or orientations (modes) in the same binding site. New forms of the 3D-QSAR correlation equations, capable of capturing this complexity, can be developed using the time hierarchy of all steps that lie behind the monitored biological process – binding, enzyme inhibition or receptor activity. In most cases, reversible interconversions of individual ligand and receptor species can be treated as quickly established equilibria because they are finished in a small fraction of the exposure time that is used to determine biological effects. The speciation equilibria are satisfactorily approximated by invariant fractions of individual ligand and receptor species for buffered experimental or in vivo conditions. For such situations, the observed drug-receptor association constant of a ligand is expressed as the sum of products, for each ligand and receptor species pair, of the association microconstant and the fractions of involved species. For multiple binding modes, each microconstant is expressed as the sum of microconstants of individual modes. This master equation leads to new 3D-QSAR correlation equations integrating the results of all molecular simulations or calculations, which are run for each ligand-receptor species pair separately. The multispecies, multimode 3D-QSAR approach is illustrated by a ligand-based correlation of transthyretin binding of thyroxine analogs and by a receptor-based correlation of inhibition of MK2 by benzothiophenes and pyrrolopyrimidines.

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Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)

Cited by 33 publications

References 66 publications

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

Improvements, trends, and new ideas in molecular docking: 2012–2013 in review

Rigorous Incorporation of Tautomers, Ionization Species, and Different Binding Modes into Ligand-Based and Receptor-Based 3D-QSAR Methods

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