An analysis of hydrophobic interactions of thymidylate synthase with methotrexate: Free energy calculations involving mutant and native structures bound to methotrexate

Reddy, R. Nageswara; Mutyala, Ravichandra; Aparoy, Polamarasetty; Reddanna, Pallu; Reddy, M. Rami

doi:10.1007/s00894-009-0535-9

Cited by 7 publications

(3 citation statements)

References 31 publications

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“…Earlier we have applied molecular dynamics simulations, and various in silico methods for COX-2 and other enzymes [ 14 , 33 , 34 , 35 , 36 , 37 ]. MD simulations and per-residue decomposition studies were performed in order to identify crucial amino acid residues for COXIB binding at the COX-2 active site [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity

Chaudhary

Aparoy

2020

Heliyon

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The enormous magnitude of scientific research carried out in the field of NSAIDs and cyclooxygenases (COXs) is known. They are crucial in pain management. COX-2 inhibitors have evolved over the years; from traditional NSAIDs to isoform-specific. The present study is aimed to identify a cluster of amino acids in the catalytic site whose energy contribution can better explain COX-2 inhibitory activity accurately than the binding energy of the whole protein. Initially, MD simulations (25 ns) and MM-PBSA calculations were performed for 8 diarylheterocyclic inhibitors. Per-residue energy decomposition studies were carried out to elucidate the energy contribution of each amino acid, and their correlation with COX-2 inhibitory activity was enumerated. A cluster of catalytic amino acids whose free energy sum has a high correlation with biological data was identified. The cluster of Gln178, Ser339, Tyr341, Arg499, Phe504, Val509 and Ala513 showed the correlation of -0.60. Further, the study was extended to a total of 26 COX-2 inhibitors belonging to different classes to validate the applicability of the cluster of amino acids identified. Results clearly suggest that the cluster of amino acids identified provide accurate screening method, and can be applied to predict COX-2 inhibitory activity of small molecules.

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Section: Introductionmentioning

confidence: 99%

Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity

Chaudhary

Aparoy

2020

Heliyon

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“…With the 3D grid spacing of 2 Å in x, y and z axis, the Coulomb potentials and the Lennard-Jones were applied to calculate the energies of steric and electrostatic field 27 . The field values of CoMFA model were detected by a probe atom of a sp 3 hybridized carbon with the value cut off set at 30 kcal/mol 28 29 . For the CoMSIA method, two additional different fields of hydrophobic, hydrogen-bond acceptor were also calculated as an extension of steric and electrostatic fields 30 .…”

Section: Methodsmentioning

confidence: 99%

Prediction and evaluation of the lipase inhibitory activities of tea polyphenols with 3D-QSAR models

Chang

Deng

et al. 2016

Sci Rep

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The extraordinary hypolipidemic effects of polyphenolic compounds from tea have been confirmed in our previous study. To gain compounds with more potent activities, using the conformations of the most active compound revealed by molecular docking, a 3D-QSAR pancreatic lipase inhibitor model with good predictive ability was established and validated by CoMFA and CoMISA methods. With good statistical significance in CoMFA (r2cv = 0.622, r2 = 0.956, F = 261.463, SEE = 0.096) and CoMISA (r2cv = 0.631, r2 = 0.932, F = 75.408, SEE = 0.212) model, we summarized the structure-activity relationship between polyphenolic compounds and pancreatic lipase inhibitory activities and find the bulky substituents in R2, R4 and R5, hydrophilic substituents in R1 and electron withdrawing groups in R2 are the key factors to enhance the lipase inhibitory activities. Under the guidance of the 3D-QSAR results, (2R,3R,2′R,3′R)-desgalloyloolongtheanin-3,3′-O-digallate (DOTD), a potent lipase inhibitor with an IC50 of 0.08 μg/ml, was obtained from EGCG oxidative polymerization catalyzed by crude polyphenol oxidase. Furthermore, DOTD was found to inhibit lipid absorption in olive oil-loaded rats, which was related with inhibiting the activities of lipase in the intestinal mucosa and contents.

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“…The steric and electrostatic field energies were calculated using the Lennard-Jones and the Coulomb potentials [26]. For CoMFA method, a sp 3 hybridized carbon atom with a+1 charge was identified as the probe atom to determine the magnitude of the steric and electrostatic field values, whose truncation was set at 30 kcal/mol [27]–[29].…”

Section: Methodsmentioning

confidence: 99%

Insight into the Interactions between Novel Isoquinolin-1,3-Dione Derivatives and Cyclin-Dependent Kinase 4 Combining QSAR and Molecular Docking

et al. 2014

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Several small-molecule CDK inhibitors have been identified, but none have been approved for clinical use in the past few years. A new series of 4-[(3-hydroxybenzylamino)-methylene]-4H-isoquinoline-1,3-diones were reported as highly potent and selective CDK4 inhibitors. In order to find more potent CDK4 inhibitors, the interactions between these novel isoquinoline-1,3-diones and cyclin-dependent kinase 4 was explored via in silico methodologies such as 3D-QSAR and docking on eighty-one compounds displaying potent selective activities against cyclin-dependent kinase 4. Internal and external cross-validation techniques were investigated as well as region focusing, bootstraping and leave-group-out. A training set of 66 compounds gave the satisfactory CoMFA model (q 2 = 0.695, r 2 = 0.947) and CoMSIA model (q 2 = 0.641, r 2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r 2 pred values of 0.875 and 0.769 for CoMFA and CoMSIA, respectively. The 3D-QSAR models generated here predicted that all five parameters are important for activity toward CDK4. Surflex-dock results, coincident with CoMFA/CoMSIA contour maps, gave the path for binding mode exploration between the inhibitors and CDK4 protein. Based on the QSAR and docking models, twenty new potent molecules have been designed and predicted better than the most active compound 12 in the literatures. The QSAR, docking and interactions analysis expand the structure-activity relationships of constrained isoquinoline-1,3-diones and contribute towards the development of more active CDK4 subtype-selective inhibitors.

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An analysis of hydrophobic interactions of thymidylate synthase with methotrexate: Free energy calculations involving mutant and native structures bound to methotrexate

Cited by 7 publications

References 31 publications

Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity

Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity

Prediction and evaluation of the lipase inhibitory activities of tea polyphenols with 3D-QSAR models

Insight into the Interactions between Novel Isoquinolin-1,3-Dione Derivatives and Cyclin-Dependent Kinase 4 Combining QSAR and Molecular Docking

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