2018
DOI: 10.1080/07391102.2018.1479309
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3D-QSAR-aided design of potent c-Met inhibitors using molecular dynamics simulation and binding free energy calculation

Abstract: Mesenchymal-epithelial transition factor (c-Met) is a member of receptor tyrosine kinase. It involves in various cellular signaling pathways which includes proliferation, motility, migration, and invasion. Over-expression of c-Met has been reported in various cancers. Hence, it is an ideal therapeutic target for cancer. The main objective of the study is to identify crucial residues involved in the inhibition of c-Met kinase and to design a series of potent imidazo [4,5-b] pyrazine derivatives as c-Met inhibit… Show more

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Cited by 13 publications
(7 citation statements)
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“…This method combines the Generalized Born (GB) electrostatics with molecular mechanics (MM) and solvent accessibility (SA) models or continuum solvent approaches, to estimate binding energies. From trajectories of MD productions, the relative change in enthalpy for the formation of the complex for the MD simulation time of 100 and 10 ns were calculated using Equations ( 4)-( 7) (Bai et al, 2020;Balasubramanian et al, 2019;Bea et al, 2006;Du et al, 2011;Greenidge et al, 2014;Greenidge et al, 2016)…”
Section: Relative Change In Binding Free Energy Calculationsmentioning
confidence: 99%
“…This method combines the Generalized Born (GB) electrostatics with molecular mechanics (MM) and solvent accessibility (SA) models or continuum solvent approaches, to estimate binding energies. From trajectories of MD productions, the relative change in enthalpy for the formation of the complex for the MD simulation time of 100 and 10 ns were calculated using Equations ( 4)-( 7) (Bai et al, 2020;Balasubramanian et al, 2019;Bea et al, 2006;Du et al, 2011;Greenidge et al, 2014;Greenidge et al, 2016)…”
Section: Relative Change In Binding Free Energy Calculationsmentioning
confidence: 99%
“…Both the far N- and C-terminal residues exhibited higher fluctuation patterns compared with the core structural residues ( Figure 12 ). This was reported as a typical thermodynamic behavior for c-Met and several kinases through molecular dynamics studies and B-factor analysis [ 109 , 110 , 111 , 137 , 138 ]. Except for a singular residue range (Ala1221-Ala1251), the four simulated c-Met ligand-bound models depicted significant immobility and stability patterns with respective ΔRSMFs being above the 0.30 cut-offs.…”
Section: Resultsmentioning
confidence: 94%
“…Consistency for ligand-directed binding towards Pro1158, Met1160, and/or Tyr1230 was reported with different c-Met inhibitors bearing quinolinylmethyl purine, dihydroquinoline, thiadiazolo [2,3-c]-triazin, and indazole scaffolds showing low-to-sub micromolar c-Met inhibition activities [ 104 , 105 , 106 , 107 , 108 ]. Studies employing quantitative structural activity relationship-aided molecular dynamics design of potent and exquisitely selective c-Met inhibitors bearing heterocyclic fused ring scaffolds [ 109 , 110 ]. These studies highlighted hydrophobic interactions with Val1092, Ala1108, Leu1157, Tyr1159, Met1211, and Tyr1230, as well as hydrogen bonding with Met1160 and Asp1222, particularly for ligands with hydrogen bond donors, for favor stabilization and free binding energy contributions.…”
Section: Resultsmentioning
confidence: 99%
“…Molecular docking, molecular dynamics, and virtual screening approaches can now be efficiently used for the design of new inhibitors of the MET kinase domain [27,56,[76][77][78][79][80]. From all these approaches, new potent compounds were obtained and more highlights revealed about MET kinase domain conformational behavior.…”
Section: Discussionmentioning
confidence: 99%