Exploring the interaction hotspots of p-glycoprotein with herbal bioactives: In silico insights for integrative...

The human multidrug resistant efflux transporter p-glycoprotein plays a crucial role in the pharmacokinetics of xenobiotics, mediating their elimination from systemic circulation. Its overexpression contributes to multidrug resistance, posing challenges to effective therapeutic interventions.

This study integrates Ayurvedic and contemporary biomedical research to investigate hotspot residues involved in the interaction of p-glycoprotein with bioactives from medicinal herbs to enhance the understanding of its substrate recognition and transport mechanisms.

The 3D structure of 6C0V was docked with 789 herbal ligand molecules utilizing the CDOCKER programme in Biovia Discovery Studio (version 4.5, 2021), revealing key residues involved in binding interactions. Alanine scanning mutagenesis was performed to evaluate the functional importance of these residues by analyzing changes in binding affinity through molecular docking.

The study identified residues Ser979, Glu972, Leu332, Phe336, Leu976, Thr76, Leu975, Gly737 and Phe732 as potential hotspots for binding and inhibition of ligand efflux into the extracellular compartment. Targeting these energetically important residues with herbal compounds can guide the development of small-molecule drugs that bind with high specificity and reduce off-target interactions, minimizing undesirable side effects.

This study provides insight into the structural basis of p-glycoprotein-herbal ligand interactions, aiding in the design of specific plant-based inhibitors for overcoming multidrug resistance in treatment of chronic diseases.