In Silico Dock of TKIs with CYP3A4 and CYP2C8 and Pharmacophore Generation

Shandong Experimental High School, Jinan, Shandong, 250001, China

Mazhenya1025@gmail.com

Abstract

Tyrosine kinase inhibitors (TKIs) serve as targeted anticancer drugs that inhibit the abnormal activity of tyrosine kinase (TK) in cancer treatment. However, when used with other medications, they often result in side effects, such as renal impairment, hepatic injury, and even mortality. This adverse clinical effect is known as drug-drug interactions (DDIs). As two major drug-related metabolic enzymes, CYP3A4 and CYP2C8 play pivotal roles in the metabolism of TKIs. To mitigate the DDIs associated with TKIs and to further develop from a clinical perspective, the interactions between TKIs and CYPs have been investigated. In this study, through docking simulations, 19 distinct TKIs were found to interact with CYP3A4, and three types of TKIs were also docked with CYP2C8. The results revealed that hydrophobic interaction and hydrogen bonds played a pivotal role in binding interaction when TKI molecules engaged with their target CYPs. Among all interacting amino acids, GLU374 and ARG105 emerged as the most critical residues for forming both hydrophobic interactions and hydrogen bonds. Afatinib, brigatinib, and nilotinib, the three TKIs docked with CYP3A4 and CYP2C8, exhibited more muscular interaction energy with CYP2C8 than with CYP3A4. The generation of common feature pharmacophores represents the unique characteristics present in each TKI. This study's findings could potentially aid medical chemists in designing and developing the next generation of TKIs while mitigating potential side effects and drug-drug interactions.