Pharmacophoric analogs of Savolitinib reveal promising inhibitors of the c-MET receptor tyrosine kinase for drug discovery: in silico investigation.

Abstract

The c-MET receptor tyrosine kinase has become a key focus for therapeutic intervention in various cancer types due to its crucial role in driving cancer progression and metastasis. While Savolitinib, a specific inhibitor of c-MET, has demonstrated promise in clinical trials, its limited availability within the body and the risk of developing resistance have prompted a quest for alternative inhibitors. In this research endeavor, we downloaded and screened a range of pharmacophoric analogs inspired by Savolitinib to explore new avenues for inhibiting c-MET. By delving into the molecular structure of Savolitinib and deciphering how it interacts with the c-MET kinase, we aimed to identify critical structural features and functional groups that could be modified to enhance its inhibitory efficacy and pharmacological properties. Employing computational modeling and pharmacokinetic assessments, this research strives to unveil novel analogs that may exhibit superior potency, selectivity, and overall drug-like attributes. Out of the 997 compounds screened, seventeen demonstrated binding energy values comparable to or greater than - 10.2 kcal/mol obtained for Savolitinib during the redocking experiment. Following a thorough evaluation via in silico ADMETox and drug-likeness prediction, two compounds, namely CID_134565115 and CID_153611202, emerged as promising candidates. They not only exhibited favorable binding energy values but also displayed a well-balanced profile concerning stability, drug-likeness and toxicity. In summary, both CID_134565115 and CID_153611202 demonstrated favorable binding energies and distinctive interaction patterns, surpassing the established Savolitinib. Although our computational study highlights the promising potential of these lead-like candidates in obstructing oncogenic c-MET signaling, further experimental investigations are necessary to verify and establish their preclinical relevance.