Inhibiting Two Cellular Mutant Epidermal Growth Factor Receptor Tyrosine Kinases By Addressing Computationally Assessed Crystal Ligand Pockets

Abstract

Aim: Blocking receptor tyrosine kinases is a useful strategy for inhibiting the overexpression of EGFR. However, the quality of crystal pocket is an essential issue for virtually identifying new leads for surviving resistance cancer cells. Results: With the examinating crystal pocket quality by the self-docking root-mean-square deviation (RMSD) calculation, we used the two best kinase pockets of mutant EGFR kinases, T790M/L858R and G719S, for virtual screening. After sorting all the docking poses of the 57,177 library compounds by consensus scores, three evidently blocked cellular EGFR phosphorylation in the H1975 and SW48 cell lines. Conclusion: The computationally assessed qualities of crystal pockets of crystal EGFR kinases can help identify new cellular active and target-specific ligands rapidly and at low cost.

Identifying New Liver X Receptor Alpha Modulators and Distinguishing Between Agonists and Antagonists By Crystal Ligand Pocket Screening

“…Such a departure from reality, if it happens in the binding site, can severely decrease the accuracy of molecular docking, and thus, the efficiency of virtual screening. Therefore, a further inspection of the 'dockable nature' [8,9] of the ligand pockets of each crystal complex is essential for molecular docking. To raise our confidence for the crystal-binding pockets of LXRα for molecular docking, we used an additional strategy, self-docking, in which a geometry-randomized crystal ligand docks back into the natural crystal-binding cavity.…”

“…DockScore [17] was then used to estimate the interaction energy between calculated ligand poses and the LXRα ligand-binding pocket. We used the same methodology and molecular docking procedure as a common base to inspect the quality of x-ray crystal-binding pockets [9]. Ligand self-docking is an important metric for evaluating docking methods [22,23] by correctly simulating the crystal ligand pose.…”

“…We emphasize the validation of the resulting RMSD for measuring the accuracy of the docking methodology and the quality of the x-ray ligand pocket. Ligand self-docking has the same procedure as mentioned [9].…”

“…To identify new LXRα modulators, we chose a suitable binding site model to conduct efficient structurebased molecular-docking screening. The molecular dockability [8,9] of the x-ray crystal ligand-binding pocket was examined by the self-docking of crystal complex ligands. If the ligand after self-docking can correctly find its crystal pose, it can indicate the dual facts that the native binding pocket and the methodology of molecular docking used are both reliable.…”

Actives-Based Receptor Selection Strongly Increases Success Rate in Structure-Based Drug Design and Leads to Identification of 22 Unique Potent Cancer Inhibitors

“…Ravindranathan and coworkers performed a virtual screening for FGFR1 which initially identified one hit compound when using our inhibitor criteria 49 . The EGFR kinase was utilized in a virtual screening study by Lee and coworkers 50 . This study proposed a significantly more intensive methodology using consensus scoring across 11 different scoring functions, resulting in the identification of four compounds having low 𝜇𝑀 IC50 values ranging from 1.53 ± 0.15 𝜇𝑀 -12.52 ± 0.37 𝜇𝑀.…”