Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors

Abstract

Human Epidermal Growth Factor Receptor-1 (EGFR), a transmembrane tyrosine kinase receptor (RTK), has been associated with several types of cancer, including breast, lung, ovarian, and anal cancers. Thus, the receptor was targeted by a variety of therapeutic approaches for cancer treatments. A series of chalcone derivatives are among the most highly potent and selective inhibitors of EGFR described to date. A series of chalcone derivatives were proposed in this study to investigate the intermolecular interactions in the active site utilizing molecular docking and molecular dynamics simulations. After a careful analysis of docking results, compounds 1a and 1d were chosen for molecular dynamics simulation study. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation revealed the ability of compounds 1a and 1d to retain the essential interactions needed for the inhibition, especially MET 93. Finally, MM-GBSA calculations highlight on the capability of the ligands to bind strongly within the active site with binding energies of −44.04 and −56.6 kcal/mol for compounds 1a and 1d, respectively. Compound 1d showed to have a close binding energy with TAK-285 (−66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease.

Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation

“…Molecular mechanics -Generalized Born solvent accessibility (MM-GBSA) method was used to calculate enthalpy for the formation of complex, number of HBs and relative change in binding free energy are conducted to deeply explore the molecular basis for the binding of complex system with screened molecules. The MM-GBSA method is based on end point method and it is efficient, reliable and broadly used to calculate accurate relative change in binding free energies (Al-Anazi et al, 2018;Balaji & Ramanathan, 2012). 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.…”

Synthesis and Anti-Cancer Activity of New Pyrazolinyl-Indole Derivatives: Pharmacophoric Interactions and Docking Studies for Identifying New EGFR Inhibitors

“…The choice of an indole-based chalcanoid infusion with the pyrazole ring as the starting molecular template was envisioned based on several studies on the anti-cancer activities of these two structural templates [ 28 , 29 , 30 ]. The role of the EGFR on certain chalcanoids has previously been discussed in an earlier report [ 31 ]. The modeled compounds, pyrazolinylindoles, at one end, were substituted by benzyl, phenoxy, and pyridyl groups, as the larger moieties selected for the binding at the EGFR-TK site possess the Met 793 residue.…”

Promising Acyclovir and its derivatives to inhibit the protease of SARS-CoV-2: Molecular Docking and Molecular Dynamics simulations

“…(Mukherjee, Patra, Barua, & Jayaram, 2011;Roe & Cheatham, 2013) Using the trajectories obtained from the MD simulation, change in enthalpy for the formation of the complex is calculated based on the equations given below. (Al-Anazi, Al-Najjar, & Khairuddean, 2018;Du et al, 2011;Greenidge, Kramer, Mozziconacci, & Sherman, 2014;Mena-Ulecia, Tiznado, & Caballero, 2015) Results And Discussion Docking In docking study, prepared target protein and compounds were loaded into ParDOCK, a web server. The binding energy for the formation of the complex with the protease of SARS-CoV-2 was calculated and given in Table 2.…”