Phytochemicals Withanolide N and Dryobalanolide as Potential Bioactive Leads for Developing Anticancer Drugs Targeting Tyrosine-Protein Kinase Mer.

There is a growing interest in harnessing natural compounds and bioactive phytochemicals to accelerate drug discovery and development, including in the treatment of human cancers. Receptor tyrosine kinases (RTKs) are critical regulators of many fundamental cellular processes and have been implicated in cancer pathogenesis as well as targets for anticancer drug development. The members of TAM, Tyro3, Axl, and MERTK subfamily RTKs, especially Mer, affect immune homeostasis in the tumor microenvironment. Hence, tyrosine-protein kinase Mer has emerged as one of the key factors in cancer susceptibility and metastasis and, by extension, as a potential target of relevance for cancer drug resistance. Here, we report, using an integrated virtual screening and simulation of phytochemicals from the IMPPAT 2.0 library, phytochemicals withanolide N and dryobalanolide as potential bioactive leads for developing anticancer drugs targeting tyrosine-protein kinase Mer. The study employed an integrated design, including physicochemical property analyses, binding affinity calculations, pan-assay interference compounds filtering, absorption, distribution, metabolism, excretion, and toxicity, and PASS analyses, in silico molecular dynamics simulations, followed by principal component analysis and free energy landscape. We call for further evaluation, validation, and translational medical research on these two phytochemicals in vitro and in vivo, with an eye to their putative therapeutic efficacy and safety in the field of oncology and anticancer drug discovery and development.