Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

Greenwood, Jeremy R.; Calkins, David R.; Sullivan, Arron; Shelley, John C.

doi:10.1007/s10822-010-9349-1

Cited by 864 publications

(654 citation statements)

References 40 publications

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“…The LigPrep module in Schrodinger 2012 suite software was introduced for geometric optimization by using OPLS_2005 force field. Ionization states of ligands were calculated with the Epik tool 37 employing Hammett and Taft methods in conjunction with ionization and tautomerization tools.…”

Section: Methodsmentioning

confidence: 99%

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

et al. 2014

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Recent crystal structures of G-protein-coupled receptors (GPCRs) have revealed ordered internal water molecules, raising questions about the functional role of those waters for receptor activation that could not be answered by the static structures. Here, we used molecular dynamics simulations to monitor-at atomic and high temporal resolutionconformational changes of central importance for the activation of three prototypical GPCRs with known crystal structures: the adenosine A 2A receptor, the b 2 -adrenergic receptor and rhodopsin. Our simulations reveal that a hydrophobic layer of amino acid residues next to the characteristic NPxxY motif forms a gate that opens to form a continuous water channel only upon receptor activation. The highly conserved tyrosine residue Y 7.53 undergoes transitions between three distinct conformations representative of inactive, G-protein activated and GPCR metastates. Additional analysis of the available GPCR crystal structures reveals general principles governing the functional roles of internal waters in GPCRs.

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Section: Methodsmentioning

confidence: 99%

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

et al. 2014

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“…For docking, the structure of the protein was prepared by Protein Preparation Wizard and the inhibitor by Ligprep [38,39] . Gulie was used to study the binding conformation between the protein and inhibitor.…”

Section: Molecular Dockingmentioning

confidence: 99%

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Mao

et al. 2015

Acta Pharmacol Sin

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Aim: Dengue is a severe epidemic disease caused by dengue virus (DENV) infection, for which no effective treatment is available. The protease complex, consisting of nonstructural protein 3 (NS3) and its cofactor NS2B, plays a pivotal role in the replication of DENV, thus may be a potential target for anti-DENV drugs. Here, we report a novel inhibitor of DENV2 NS2B/NS3 protease and its antiviral action. Methods: An enzymatic inhibition assay was used for screening DENV2 NS2B/NS3 inhibitors. Cytotoxicity to BHK-21 cells was assessed with MTT assay. Antiviral activity was evaluated in BHK-21 cells transfected with Rlu-DENV-Rep. The molecular mechanisms of the antiviral action was analyzed using surface plasmon resonance, ultraviolet-visible spectral analysis and differential scanning calorimetry assays, as well as molecular docking analysis combined with site-directed mutagenesis. Results: In our in-house library of old drugs (~1000 compounds), a topical hemostatic and antiseptic 2-hydroxy-3,5-bis[(4-hydroxy-2-methyl-5-sulfophenyl)methyl]-4-methyl-benzene-sulfonic acid (policresulen) was found to be a potent inhibitor of DENV2 NS2B/NS3 protease with IC 50 of 0.48 μg/mL. Furthermore, policresulen inhibited DENV2 replication in BHK-21 cells with IC 50 of 4.99 μg/mL, whereas its IC 50 for cytotoxicity to BHK-21 cells was 459.45 μg/mL. Policresulen acted as a competitive inhibitor of the protease, and slightly affected the protease stability. Using biophysical technology-based assays and molecular docking analysis combined with sitedirected mutagenesis, we demonstrated that the residues Gln106 and Arg133 of DENV2 NS2B/NS3 protease directly interacted with policresulen via hydrogen bonding. Conclusion: Policresulen is a potent inhibitor of DENV2 NS2B/NS3 protease that inhibits DENV2 replication in BHK-21 cells. The binding mode of the protease and policresulen provides useful hints for designing new type of inhibitors against the protease.

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“…Quantum-chemical calculations are a very suitable tool to study the tautomeric compounds, but the results always remain captive on the level of theory and basis set used [1,2]. This is especially true for the description of systems, where the tautomers co-exist in solution.…”

Section: Introductionmentioning

confidence: 99%

Tautomerism in 1-phenylazo-4-naphthols: Experimental results vs quantum-chemical predictions

et al. 2012

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The reliability in the description of the tautomerism of 1-phenylazo-4-naphthol by using of HF and MP2 ab initio levels of theory and DFT methods with variety of pure GGA (OLYP), hybrid (B3LYP and B3PW91), long range corrected (LC-BLYP) and double-hybrid (B2PLYP and mPW2PLYP) functionals with large number of basis sets was estimated. In this evaluation three criteria were used: reproduction of the bond lengths in the structures of the individual tautomers, description of the non-planarity of the enol tautomer and prediction of the position of the tautomeric equilibrium (ΔG value) at 298 K. The results show that in substantial number of cases HF reasonably covers all requirements. The tested pure (OLYP) and hybrid functionals (B3LYP and B3PW91) fail in the prediction of the position of the equilibrium independent on the basis set. The situation is slightly better at the long range corrected functional (LC-BLYP), which give predominance of the enol tautomer at 6-31þG** and D95þþ**. The double hybrid functionals give very good description with D95þþ** basis set, but at substantial computational costs.

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Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

Cited by 864 publications

References 40 publications

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Tautomerism in 1-phenylazo-4-naphthols: Experimental results vs quantum-chemical predictions

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