Importance of Accurate Charges in Binding Affinity Calculations: A Case of Neuraminidase Series

Park, Kichul; Sung, Nack Kyun; Cho, Art E.

doi:10.5012/bkcs.2013.34.2.545

Cited by 13 publications

(11 citation statements)

References 32 publications

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“…Prior to molecular docking, the geometries of the compounds were quantum-mechanically (QM)-optimized using GAMESS-US [ 37 ] software (B3LYP/6-31G*). The optimized structures of the ligands were used with partial atomic charges derived from QM results [ 38 , 39 , 40 , 41 ] according to the Mulliken scheme [ 42 ] without torsion or any other degree of freedom for the ligands, which were frozen for molecular docking.…”

Section: Methodsmentioning

confidence: 99%

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

et al. 2020

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In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

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Section: Methodsmentioning

confidence: 99%

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

et al. 2020

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“…5,10 The correlation with experimental binding affinities was considerably improved with QPLD compared to Glide SP/XP. 31 Hence, the obtained better posed seed structures in RRD were further investigated through quantum-polarized ligand docking (QPLD) using Q-Site module at the B3LYP/6-31G* level, which yield excellent results for atomization energies and transition states in a wide range of chemical systems. 31 Afterwards, we ranked when comparing their binding affinities (kcal mol À1 ) of QPLD leads against pre-existing inhibitors (positive controls) as the best decisions to adaptable docking.…”

Section: Quantum Mechanics and Molecular Mechanics (Qm/ Mm) In Dockinmentioning

confidence: 99%

Hierarchical-Clustering, Scaffold-Mining Exercises and Dynamics Simulations for Effectual Inhibitors Against Lipid-A Biosynthesis of Helicobacter pylori

et al. 2019

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Introduction-Treatment failures of standard regimens and new strains egression are due to the augmented drug resistance conundrum. These confounding factors now became the drug designers spotlight to implement therapeutics against Helicobacter pylori strains and to safeguard infected victims with devoid of adverse drug reactions. Thereby, to navigate the chemical space for medicine, paramount vital drug target opting considerations should be imperative. The study is therefore aimed to develop potent therapeutic variants against an insightful extrapolative, common target LpxC as a follow-up to previous studies. Methods-We explored the relationships between existing inhibitors and novel leads at the scaffold level in an appropriate conformational plasticity for lead-optimization campaign. Hierarchical-clustering and shape-based screening against an in-house library of > 21 million compounds resulted in panel of 11,000 compounds. Rigid-receptor docking through virtual screening cascade, quantum-polarized-ligand, induced-fit dockings, post-docking processes and system stability assessments were performed. Results-After docking experiments, an enrichment performance unveiled seven ranked actives better binding efficiencies with Zinc-binding potency than substrate and in-actives (decoy-set) with ROC (1.0) and area under accumulation curve (0.90) metrics. Physics-based membrane permeability accompanied ADME/T predictions and long-range dynamic simulations of 250 ns chemical time have depicted good passive diffusion with no toxicity of leads and sustained consistency of lead1-LpxC in the physiological milieu respectively. Conclusions-In the study, as these static outcomes obtained from this approach competed with the substrate and existing ligands in binding affinity estimations as well as positively correlated from different aspects of predictions, which could facilitate promiscuous new chemical entities against H. pylori.

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“…It is now well recognized that the accuracy of electronic charges and environmental polarization play a crucial role in ligand-protein docking (Illingworth et al, 2008;Park et al, 2013). A number of studies have indicated that recalculating atomic charges by the hybrid quantum mechanical/molecular mechanical (QM/MM) method can significantly improve the accuracy of the prediction of docking poses (Du et al, 2011;Cho et al, 2005;Cho & David, 2010).…”

Section: Introductionmentioning

confidence: 99%

The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen-bond scoring strategy

Kurczab

2017

Acta Crystallogr B Struct Sci Cryst Eng Mater

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The combination of quantum mechanics/molecular mechanics-driven (QM/MM) molecular docking with binding free-energy calculations was successfully used to reproduce the X-ray geometries of protein-ligand complexes with halogen bonding. The procedure involves quantum-polarized ligand docking (QPLD) to obtain the QM-derived ligand atomic charges in the protein environment at the B3PW91/cc-pVTZ level and the MM/GBSA (generalized-Born/surface area) algorithm to calculate the binding free energies of resultant complexes. The performance was validated using a set of 106 X-ray complexes and compared with the Glide and AutoDock VinaXB scoring functions in terms of RMSD and the reconstruction of halogen-bond geometry (distance and σ-hole angle). The results revealed that docking and scoring using the QPLD-GBSA procedure outperformed the remaining scoring functions in the majority of instances. Additionally, a comparison of the orientation of the top ranked binding poses calculated using the fixed atomic charges of ligands obtained from force-field parameterization and by QM calculations in the protein environment provides strong evidence that the use of QM-derived charges is significant.

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Importance of Accurate Charges in Binding Affinity Calculations: A Case of Neuraminidase Series

Cited by 13 publications

References 32 publications

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

Hierarchical-Clustering, Scaffold-Mining Exercises and Dynamics Simulations for Effectual Inhibitors Against Lipid-A Biosynthesis of Helicobacter pylori

The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen-bond scoring strategy

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