Turkish Computational and Theoretical Chemistry

Abstract

Tyrosine kinases are considered as major target in the treatment of cancer as they regulate various cellular metabolic pathways. SRC tyrosine kinase is one of the key enzyme involved in various cellular processes and is considered a promising therapeutic target for cancer treatment. In silico computational studies were carried out to evaluate the potential of pyrazole, indazole, and imidazopyridine analogs as SRC (commonly known for c-SRC, pronounced as a short form of sarcoma) kinase inhibitors. Molegro Virtual Docker version 2019.7.0.0-2019-03-18 was used to screen a large number of pyrazole, indazole, and imidazopyridine analogs. The top ligands were selected based on their binding affinity and further analyzed for their interactions with the SRC kinase binding site. The results showed that many of the analogs interacted with key amino acid residues of the DFG motif, Asp-404, Phe-405, and Gly-406, and the hinge region, Glu-339, Tyr-340, and Met-341 including gatekeeper residue Thr-338 of the enzyme. In silico ADMET studies were performed to assess the pharmacokinetic and toxicological properties of the selected ligands. The results indicated that most of the ligands had good oral absorption and favorable protein binding. However, some ligands showed potential toxicity, including hepatotoxicity and drug-induced liver injury. MD Simulations were conducted to study the stability and interactions between the ligands and SRC kinase over a 25 ns period. The simulations revealed that most of the complexes remained stable, and the best ones are 71588244 and 70736676. The findings suggest that these analogs could be further developed as potential therapeutic agents for the treatment of cancer.