Designing of CHK1 Inhibitors by 3d-QSAR, Virtual Screening and Induced Fit Docking Studies

Chavan, Sayalee R.; Hirwani, Rajkumar; Alam, M. Sarwar; Vidyasagar, Nikhil; Dash, Radha Charan; Deshpande, V. N.

doi:10.18520/v109/i12/2271-2277

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“…Macromolecule-based VS utilizes a molecular docking technique that aids understanding of the three-dimensional (3D) structure of the target protein binding site. In numerous instances including those involving break-point cluster region-abelson murine leukemia (BCR-ABL) TK [ 15 ], checkpoint kinase 1(Chk1) [ 16 ], FK506 binding protein (FKBP) [ 17 ], and protein tyrosine phosphatases [ 18 ], structure-based VS methods have been helpful in identifying new inhibitors. A few EGFR-TK receptor-based VS studies against industrial and commercial chemical compounds in the anilinoquinazoline, pyridopyrimidine, and pyrrolopyrimidine families have been described [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and in vitro evaluation

Radwan,

Alanazi,

Al-Dhfyan

2024

PLoS ONE

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Epidermal growth factor receptor EGFR inhibitors are widely used as first line therapy for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR mutation. However, the acquisition of a second-site mutation (T790 M) limited the efficacy and developed resistance. Therefore, discovery and development of specific drug target for this mutation is of urgent needs. In our study we used the ChemDiv diversity database for receptor-based virtual screening to secure EGFR-TK inhibitors chemotherapeutics. We identified four compounds that bind to the ATP-binding region of the EGFR-TK using AutoDock 4.0 and AutoDock Vina1.1.2 and post-docking investigations. The ligand showed hydrophobic interactions to the hydrophobic region of the binding site and engaged in hydrogen bonding with Met793. The ligands also explored π–cation interactions between the π-system of the ligand–phenyl ring and the positive amino group of Lys745. Molecular mechanics Poisson–Boltzmann surface area MM/PBSA per-residue energy decomposition analyses revealed that Val726, Leu792, Met793, Gly796, Cys797, Leu798, and Thr844 contributed the most to the binding energy. Biological evaluation of the retrieved hit compounds showed suppressing activity against EGFR auto phosphorylation and selective apoptosis-induced effects toward lung cancer cells harboring the EGFR L858R/T790M double mutation. Our work anticipated into novel and specific EGFR-TKIs and identified new compounds with therapeutic potential against lung cancer.

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