Docking and Molecular Dynamics Calculations of Pyrrolidinone Analog MMK16 Bound to COX and LOX Enzymes

Neophytou, Niki; Leonis, Georgios; Stavrinoudakis, N.; Simčič, Mihael; Grdadolnik, Simona Golič; Papavassilopoulou, Eleni; Michas, Georgios; Moutevelis‐Minakakis, Panagiota; Παπαδόπουλος, Μάνθος Γ.; Zing, M.; Mavromoustakos, Thomas

doi:10.1002/minf.201000131

Cited by 9 publications

(3 citation statements)

References 53 publications

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“…Numerous COX-2 inhibitors have been developed over the years. Structural details of the COX-2 enzyme and the binding mode of its inhibitors were explained previously employing various in silico methods like molecular docking and molecular dynamics simulation studies [ 14 , 20 , 21 , 22 , 23 , 24 ]. Generally, COX-2 inhibitors are classified into two major classes on the basis of number of ring structures: (1) Tricyclic or Diarylheterocyclic compounds which possess two proximal diaryl moieties linked to a central heterocyclic or carbocyclic ring; the compounds in this class mainly differ from one another in the central aromatic ring which can either be 4-membered (cyclobutene), 5-membered (pyrazole, isoxazole, furanone) or 6-membered (pyridine, pyranone) [ 25 ]; (2) Non-tricyclic compounds: This class of compounds lacks the central cyclic ring.…”

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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“…8 Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task. Work is underway to find potential NSAIDs among substances of natural origin, 9 as well as synthetic derivatives of azepine, 10 benzimidazole, 11,12 triazole, [13][14][15] 1,3,4-oxadiazole, [16][17][18][19][20] xanthone, 21 coumarin, [22][23][24] quinazoline, 25,26 pyrrolidinone, 27,28 pyrrolisine, 29 pyrazole, [30][31][32] 1,3-thiazole, 33 pyridazine, 34 and other cyclic and acyclic systems. 35 Recently, pyrimidine derivatives have been of increasing interest as potential COX inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Anti-Inflammatory Activity and Molecular Docking Studies of 1,4,5,6-Tetrahydropyrimidine-2-Carboxamides

et al. 2020

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Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors. Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task. Methods: This work studied the synthesis of new 1,4,5,6-tetrahydropyrimidine-2-carboxamides based on the reaction of 2-morpholin-4-yl-N-(het)aryl-2-thioxoacetamides with 1,3-diaminopropane. All obtained compounds were tested for anti-inflammatory activity in vitro and in silico conditions. All synthesized 1,4,5,6-tetrahydropyrimidine-2-carboxamides were tested for influence on the course of the exudative phase of the inflammatory process based on the carrageenan model of paw edema of laboratory nonlinear heterosexual white rats weighing 220-250 g, using Diclofenac as a reference. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package. Results: The target products were obtained with yields of 71-98% and easily isolated from the reaction mixture. The best anti-inflammatory activity was found in N-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine-2-carboxamide and in N-[4-chloro-3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine-2-carboxamide, suppression of the inflammatory response was 46.7 and 46.4%, respectively. The results of molecular docking with COX-1 and COX-2 enzymes were in good agreement with the experimental data, R2 ˃ 0.92 and R2 ˃ 0.83, respectively. Conclusion: The compounds under study were shown to be promising as potential anti-inflammatory agents.

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“…Many NSAIDs inhibit both COX1 and COX2 enzymes and reduces inflammation, damaging the lining of the stomach leading to gastric problems like stomach upset, ulceration and blood bleeding from the stomach and intestine. Antagonizing specific COX2 enzyme is an attractive therapeutic target to develop potent anti-inflammatory drugs [4].…”

Section: Introductionmentioning

confidence: 99%

Isolation of Compounds from <i>Sargassum wightii </i> by GCMS and the Molecular Docking against Anti-Inflammatory Marker COX2

Balachandran

Parthasarathy

Kumar

2016

ILCPA

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ABSTRACT. The study focused on the molecular docking of GC-MS isolated compounds from the Sargassum wightii against inflammatory marker Cycloxigenase-2 (COX2). Seven compounds isolated by GC-MS were tested for their anti-inflammatory action using insilico analysis. The crystal structure obtained from the protein data bank was docked against seven compounds and the glide score as well as glide energy were determined using Schrödinger Maestro software (version 2013.1). The results of molecular docking showed that out of the seven bioactive compounds tested, methyl salicylate, benzoic acid, 2-hydroxy-,ethyl ester, diethyl phthalate, hexadecanoic acid, ethyl ester and (E) -9-octadecenoic acid ethyl ester were effectively inhibited the COX2 protein. The ADME properties of the compounds analyzed using Qikprop version 3.6 software of Schrodinger suite and the results showed that all the compounds were biologically active and the scores were within the acceptable range. This study revealed that the possibility of using these compounds against COX2 to treat inflammation.

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Docking and Molecular Dynamics Calculations of Pyrrolidinone Analog MMK16 Bound to COX and LOX Enzymes

Cited by 9 publications

References 53 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

Synthesis, Anti-Inflammatory Activity and Molecular Docking Studies of 1,4,5,6-Tetrahydropyrimidine-2-Carboxamides

Isolation of Compounds from <i>Sargassum wightii </i> by GCMS and the Molecular Docking against Anti-Inflammatory Marker COX2

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