Discovery of potential epidermal growth factor receptor inhibitors from black pepper for the treatment of lung cancer: an in-silico approach.

A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is one of the main tumour markers in many cancer types and also plays a crucial role in cell proliferation, differentiation, angiogenesis, and apoptosis, which is a result of the auto-phosphorylations (kinase activity enhancement) that trigger signals involved in different cellular processes. Due to the discovery that non-small cell lung cancer (NSCLC) is a cause of this kinase activity enhancement, so far, several inhibitors have been tested against EGFR, but the side effects of these inhibitors necessitate an urgent measure to come up with an inhibitor that will be more specific to the cancer cells and not affect self-cells. This study was conducted to evaluate the efficacy of 37 compounds derived from Piper nigrum against EGFR using computer-aided drug design. Based on molecular docking, induced-fit docking, calculation of free binding energy, pharmacokinetics, QSAR prediction, and MD simulation. We propose five (5) lead compounds (clarkinol A, isodihydrofutoquinol B, Burchellin, kadsurin B, and lancifolin C) as a novel inhibitor, with clarkinol A demonstrating the highest binding affinity (-7.304 kcal/mol) with EGFR when compared with the standard drug (erlotinib). They also showed significant moderation for parameters investigated for a good pharmacokinetic profile, with a reliable R2 coefficient value predicted using QSAR models. The MD simulation of clarkinol A was found to be stable within the EGFR binding pocket throughout the 75 ns simulation run time. The findings showed that clarkinol A derived from Piper nigrum is worth further investigation and consideration as a possible EGFR inhibitor for the treatment of lung cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00197-1.

Insight into the Nucleotide Based Modulation of the Grp94 Molecular Chaperone Using Multiscale Dynamics.

Grp94, an ER-localized molecular chaperone, is required for the folding and activation of many membrane and secretory proteins. Client activation by Grp94 is mediated by nucleotide and conformational changes. In this work, we aim to understand how microscopic changes from nucleotide hydrolysis can potentiate large-scale conformational changes of Grp94. We performed all-atom molecular dynamics simulations on the ATP-hydrolysis competent state of the Grp94 dimer in four different nucleotide bound states. We found that Grp94 was the most rigid when ATP was bound. ATP hydrolysis or nucleotide removal enhanced mobility of the N-terminal domain and ATP lid, resulting in suppression of interdomain communication. In an asymmetric conformation with one hydrolyzed nucleotide, we identified a more compact state, similar to experimental observations. We also identified a potential regulatory role of the flexible linker, as it formed electrostatic interactions with the Grp94 M-domain helix near the region where BiP is known to bind. These studies were complemented with normal-mode analysis of an elastic network model to investigate Grp94's large-scale conformational changes. SPM analysis identified residues that are important in signaling conformational change, many of which have known functional relevance in ATP coordination and catalysis, client binding, and BiP binding. Our findings suggest that ATP hydrolysis in Grp94 alters allosteric wiring and facilitates conformational changes.