In silico screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 as potential MDR reversal agents.

Purpose: Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using in silico studies.

Methods: Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations.

Results: Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results.

Conclusion: We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.