In silico search of triple mutant T790M/C797S allosteric inhibitors to conquer acquired resistance problem in non-small cell lung cancer (NSCLC): a combined approach of structure-based virtual screening and molecular dynamics simulation

In-silico Studies Calculated a New Chitin Oligomer Binding Site Inside Vicilin: A Potent Antifungal and Insecticidal Agent

“…The Nose–Hoover thermostat algorithm and Martyna–Tobias–Klein Barostat algorithm were used to maintain the constant temperature (300 K) and pressure 1 atm respectively during simulation. 34 - 36 Molecular simulations of both native protein and docked complex were done for 50 ns and comparative analysis was performed to understand the structural stability of protein and protein-ligand complex, and following quality parameters; Root Mean Square Deviation (RMSD), Root Mean Square Fluctuations (RMSF), Radius of Gyration (RoG), intermolecular hydrogen bonds (H-bonds) and Solvent Accessible Surface Area (SASA), were calculated. PyMOL was used for analyzing the MD simulation results of both bounded and unbounded forms of protein.…”

In silico validation of anti-viral drugs obtained from marine sources as a potential target against SARS-CoV-2 Mpro

“…Noose-Hover chain thermostat algorithm at 300 K, Martyna-Tobias-Klein barostat algorithm at 1.01325 bar, isotropic coupling, Coulombic cut off at 0.9 nm. The rest of the parameters were default [ 58 , 59 ]. The trajectories of MD simulations evaluated for ligand-receptor interactions were identified using the Simulation Interaction Diagram (SID) tool.…”

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer

“…On March 30, 2017, the US Food and Drug Administration (FDA) conceded regular approval to Osimertinib (AZD9291) for the management of patients with metastatic “EGFR-T790M Non-Small Cell Lung Cancer (NSCLC)”. , The FDA-approved drug Osimertinib is at the forefront for the treatment of NSCLC patients (Figure ). − However, a significant proportion of Osimertinib-treated patients developed the EGFR kinase tertiary cystein 797 to serine 797 (C797S) mutation by the loss of covalent binding with the Cys797 residue, which renders a resistance to all the existing drugs. , Additional studies with mutant cell lines have shown that the allelic context of the activating gatekeeper and C797S mutations affects the sensitivity of three generations of EGFR inhibitors, with no epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) alone or in combination able to suppress activity when the mutation is in the cis -form. − These data suggest that there is a pressing need for drugs that can overcome the ternary mutation (L858R/T790M/C797S EGFR) obstacle in NSCLC . The crystallographic structure of C797S-EGFR revealed that the C797S mutation has no effect on the EGFR kinase’s structure or function but does increase the degree of local hydrophilicity around residue 797 (Figure ).…”