Investigating Natural Inhibitors of Permeability-Glycoprotein (P-gp) Liver Transporter via Molecular Docking Simulation for Hepatocellular Carcinoma Therapy
5th International Conference on Soft Computing and its Engineering Applications, icSoftComp 2023, Changa, Hindistan, 7 - 09 Aralık 2023, cilt.2030, ss.81-93, (Tam Metin Bildiri)
- Yayın Türü: Bildiri / Tam Metin Bildiri
- Cilt numarası: 2030
- Doi Numarası: 10.1007/978-3-031-53731-8_7
- Basıldığı Şehir: Changa
- Basıldığı Ülke: Hindistan
- Sayfa Sayıları: ss.81-93
- Anahtar Kelimeler: Xenobiotics, P-gp protein, natural compound inhibitors, molecular docking, hepatocellular carcinoma (HCC) therapy, Hepatotoxicity, QSAR Toxicity assessment
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
Permeability-glycoprotein (P-gp), a dynamic efflux pump responsible for transporting xenobiotics and drugs out of cells, is a contributor to multidrug resistance (MDR), a pervasive challenge in therapeutic efficacy. In Hepatocellular Carcinoma (HCC), chemotherapy failures are often attributed to both multi-drug resistance and mounting evidence spotlighting the multi-drug resistance protein-1 (MDR1, also recognized as P-gp) as a pivotal determinant of chemotherapy resistance in HCC. Aligned with the FDA’s 2020 directives, the investigation of P-gp inhibition has been mandated for Drug-Drug Interaction (DDI) assessments, hepatotoxicity evaluations, and therapeutic contexts. Yet, a prevalent experimental technique poses a hurdle. The FDA-endorsed MDCK-MDR1 cell-based permeability assay, while valuable for discerning and characterizing P-gp inhibitors, grapples with limited throughput and high expenses, amounting to ~10,000 € per compound. In response to these challenges, we introduce a pioneering approach that harnesses molecular docking to uncover potential natural inhibitors of the P-gp liver transporter. Our molecular docking outcomes unearth profound insights. Noteworthy reference drugs, Elacridar (−10.70 kcal/mol) and Zosuquidar (−10.50 kcal/mol), exhibit substantial affinities. Furthermore, our inquiry pinpoints a cluster of natural compounds boasting robust affinities against P-gp, with projections as potential inhibitors with binding energies of ~10.50 kcal/mol. Our in-silico methodology navigates the domain of natural P-gp inhibitors, furnishing an extensive comprehension of intricate interactions between inhibitor compounds and P-gp protein. This innovative approach holds the promise of a cost-effective substitute for prevailing screening methods. It could potentially pave the path toward devising efficacious strategies combating P-gp-driven MDR in the realm of HCC therapy.