Computational identification of 2,4-disubstituted amino-pyrimidines as L858R/T790M-EGFR double mutant inhibitors using pharmacophore mapping, molecular docking, binding free energy calculation, DFT study and molecular dynamic simulation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Rahul Pawara ◽  
Iqrar Ahmad ◽  
Sanjay Surana ◽  
Harun Patel
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamic Simulation ◽  
Dynamic Simulation ◽  
Double Mutant ◽  
Binding Free Energy ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Pharmacophore Mapping ◽  
Computational Identification

scholarly journals Structure-Based Virtual Screening and Molecular Dynamic Simulation Studies to Identify Novel Cytochrome bc1 Inhibitors as Antimalarial Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Rahul P. Gangwal ◽  
Gaurao V. Dhoke ◽  
Mangesh V. Damre ◽  
Kanchan Khandelwal ◽  
Abhay T. Sangamwar
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamic Simulation ◽  
Molecular Dynamic ◽  
Dynamic Simulation ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Van Der Waals Interactions ◽  
Electrostatic Energy ◽  
Hydrogen Bond Acceptor

Cytochrome bc1 (EC 1.10.2.2, bc1) is an essential component of the cellular respiratory chain, which catalyzes electron transfer from quinol to cytochrome c and concomitantly the translocation of protons across the membrane. It has been identified as a promising target in malaria parasites. The structure-based pharmacophore modelling and molecular dynamic simulation approach have been employed to identify novel inhibitors of cytochrome bc1. The best structure-based pharmacophore hypothesis (Hypo1) consists of one hydrogen bond acceptor (HBA), one general hydrophobic (HY), and two hydrophobic aromatic features (HYAr). Further, hydrogen interactions and hydrophobic interactions of known potent inhibitors with cytochrome bc1 were compared with Hypo1, which showed that the Hypo1 has good predictive ability. The validated Hypo1 was used to screen the chemical databases. The hits obtained were subsequently subjected to the molecular docking analysis to identify false-positive hits. Moreover, the molecular docking results were further validated by molecular dynamics simulations. Binding-free energy analysis using MM-GBSA method reveals that the van der Waals interactions and the electrostatic energy provide the basis for favorable absolute free energy of the complex. The five virtual hits were identified as possible candidates for the designing of potent cytochrome bc1 inhibitors.

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