Predicting the Prevalence of Alternative Warfarin Tautomers in Solution

Malde, Alpeshkumar K.; Stroet, Martin; Caron, Bertrand; Visscher, Koen; Mark, Alan E.

doi:10.1021/acs.jctc.8b00453

Cited by 15 publications

(13 citation statements)

References 57 publications

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“…Fitting artefacts associated with assigning ESP charges based on the use of a single configuration were mitigated by averaging the resulting charges for chemically equivalent atoms. 43 Chemically equivalent atoms within a given moleculearising as a result of molecular symmetry or rapid exchange-were identified from the automorphic nodes of the corresponding molecular graph calculated using the package nauty. 44…”

Section: Parameterization Algorithmmentioning

confidence: 99%

Automated Topology Builder Version 3.0: Prediction of Solvation Free Enthalpies in Water and Hexane

Stroet

Caron

Visscher

et al. 2018

J. Chem. Theory Comput.

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362

230

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The ability of atomic interaction parameters generated using the Automated Topology Builder and Repository version 3.0 (ATB3.0) to predict experimental hydration free enthalpies (DG water) and solvation free enthalpies in the apolar solvent hexane (DG hexane) is presented. For a validation set of 685 molecules the average unsigned error (AUE) between DG water values calculated using the ATB3.0 and experiment is 3.9 kJ•mol-1. The slope of the line of best fit is 1.00, the intercept-1.0 kJ•mol-1 and the R 2 0.90. For the more restricted set of 239 molecules used to validate OPLS3 (J. Chem. Theory Comput. 2016, 12, 281-296.) the AUE using the ATB3.0 is just 2.7 kJ•mol-1 and the R 2 0.93. A roadmap for further improvement of the ATB parameters is presented together with a discussion of the challenges of validating force fields against the available experimental data.

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Section: Parameterization Algorithmmentioning

confidence: 99%

Automated Topology Builder Version 3.0: Prediction of Solvation Free Enthalpies in Water and Hexane

Stroet

Caron

Visscher

et al. 2018

J. Chem. Theory Comput.

Self Cite

362

230

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“…Warfarin exists in roughly 40 tautomeric forms, [9,10] though two forms, keto and hemiketal, are major contributors (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis, Computational Molecular Docking and Invitro Anticoagulant Activity of Warfarin-Based Derivatives

Afzal

Rashid

Nadeem

et al. 2022

Preprint

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Warfarin containing coumarin ring system possesses excellent anticoagulant activity in its enantiomeric form (S). The present work designed to synthesize warfarin based derivatives enantioselectivily to explore their anticoagulant potential. The substituted chalcones were reacted with 4-OH coumarin in presence of chiral catalyst 9-amino-9-deoxyepiquinine to afford warfarin based analogues 5a-5k. The structures of synthesized compounds 5a-5k were confirmed by FTIR, 1HNMR,13CNMR and EIMS data. The enantioselectivity has been assured by determining the enantiomeric excess (ee) in chiral HPLC which exhibited 16-99%ee. The invitro anticoagulant activity of synthesized compounds 5a-5k was evaluated by plasma recalcification time (PRT) method and it was found that most of the derivatives showed good anticoagulant activity specifically compound 5b exhibited excellent results compared to warfarin. The compound 5b displayed IC50 value 249.88µM better than standard warfarin (IC50 408.70µM). The molecular docking studies has been performed against vitamin K epoxide reductase with PDBID 3kp9. The synthesized compounds binds well in active binding site of target enzyme. The derivative 5b showed pi-stacking interactions with amino acid phenylalanine (PHE A 114).The antimicrobial activity of synthesized compounds has also been performed and results showed moderate antimicrobial activity. Based upon our results it is proposed derivative 5b may act as lead compound to design more potent anticoagulant derivatives.

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“…Perturbation free-energy calculations, involving alchemical transformation of one chemical into another via a pathway of unphysical intermediate states, present a rigorous approach derived from statistical mechanics. [1][2][3][4][5][6][7][8][9][10][11][12] Several such methods have been developed over the years, including for instance thermodynamic integration, 13 its extended version 14 or Bennett's acceptance ratio. 15 More recently, non-equilibrium techniques like the Crooks Gaussian intersection method 16 and the Jarzynski equality, 17 have also been applied.…”

Section: Introductionmentioning

confidence: 99%

Perturbation Free-Energy Toolkit: Automated Alchemical Topology Builder and Optimized Simulation Update Scheme

Petrov

2021

Preprint

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Free-energy calculations play an important role in the application of computational chemistry to a range of fields, including protein biochemistry, rational drug design or material science. Importantly, the free energy difference is directly related to experimentally measurable quantities such as partition and adsorption coefficients, water activity and binding affinities. Among several techniques aimed at predicting the free-energy differences, perturbation approaches, involving alchemical transformation of one molecule into another through intermediate states, stand out as rigorous methods based on statistical mechanics. However, despite the importance of efficient and accurate free energy predictions, applicability of the perturbation approaches is still largely impeded by a number of challenges. This study aims at addressing two of them: 1) the definition of the perturbation path, i.e., alchemical changes leading to the transformation of one molecule to the other, and 2) determining the amount of sampling along the path to reach desired convergence. In particular, an automatic perturbation builder based on a graph matching algorithm is developed, that is able to identify the maximum common substructure of two molecules and provide the perturbation topologies suitable for free-energy calculations using GROMOS and GROMACS simulation packages. Moreover, it was used to calculate the changes in free energy of a set of post-translational modifications and analyze their convergence behavior. Different methods were tested, which showed that MBAR and extended thermodynamic integration (TI) in combination with MBAR show better performance as compared to BAR, extended TI with linear interpolation and plain TI. Also, a number of error estimators were explored and how they relate to the true error, estimated as the difference in free energy from an extensive set of simulation data. This analysis shows that most of the estimators provide only a qualitative agreement to the true error, with little quantitative predictive power. This notwithstanding, the preformed analyses provided insight into the convergence of free-energy calculations, which allowed for development of an iterative update scheme for perturbation simulations that aims at minimizing the simulation time to reach the convergence, i.e., optimizing the efficiency. Importantly, this toolkit is made available online as an open-source python package (https://github.com/drazen-petrov/SMArt).

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Predicting the Prevalence of Alternative Warfarin Tautomers in Solution

Cited by 15 publications

References 57 publications

Automated Topology Builder Version 3.0: Prediction of Solvation Free Enthalpies in Water and Hexane

Automated Topology Builder Version 3.0: Prediction of Solvation Free Enthalpies in Water and Hexane

Enantioselective Synthesis, Computational Molecular Docking and Invitro Anticoagulant Activity of Warfarin-Based Derivatives

Perturbation Free-Energy Toolkit: Automated Alchemical Topology Builder and Optimized Simulation Update Scheme

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