Journal Article

Computationally accelerated identification of P-glycoprotein inhibitors

Wise, John G., Vogel, Pia D., McCormick, Lauren A., McCormick, James W., Park, Chanyang, Follit, Courtney A.

2025

Overview

Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ABCB1 ), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump’s transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump’s cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ABC transporters / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antineoplastic drugs / ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors / ATP Binding Cassette Transporter, Subfamily B - chemistry / ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors / ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry / ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism / Binding / Biology and Life Sciences / Cancer / Cancer therapies / Chemotherapy / Clinical trials / Computational biology / Drug development / Drug discovery / Drug Discovery - methods / Drug dosages / Drug resistance / Drug Resistance, Multiple - drug effects / Drug Resistance, Neoplasm - drug effects / Efflux / Enzyme inhibitors / Glycoproteins / Health aspects / Homology / Humans / Identification and classification / Inhibitors / Medicine and Health Sciences / Methods / Molecular docking / Molecular Docking Simulation / Molecular dynamics / Molecular Dynamics Simulation / Multidrug resistance / Nucleotides / P-Glycoprotein / Pharmacokinetics / Physical Sciences / Physiological aspects / Research and Analysis Methods / Simulation / Substrate inhibition / Toxicity / Tumor cell lines