P-glycoprotein (P-gp) is a plasma membrane efflux transporter belonging to ATP-binding cassette superfamily, responsible for multidrug resistance in tumor cells. Over-expression of P-gp in cancer cells limits the efficacy of many anticancer drugs. A clear understanding of P-gp substrate binding will be advantageous in early drug discovery process. However, substrate poly-specificity of P-gp is a limiting factor in rational drug design. In this investigation, we report a dynamic trans-membrane model of P-gp that accurately identified the substrate binding residues of known anticancer agents. The study included homology modeling of human P-gp based on the crystal structure of C. elegans P-gp, molecular docking, molecular dynamics analyses and binding free energy calculations. The model was further utilized to speculate substrate propensity of in-house anticancer compounds. The model demonstrated promising results with one anticancer compound (NSC745689). As per our observations, the molecule could be a potential lead for anticancer agents devoid of P-gp mediated multiple drug resistance. The in silico results were further validated experimentally using Caco-2 cell lines studies, where NSC745689 exhibited poor permeability (P app 1.03 ± 0.16 × 10(-6) cm/s) and low efflux ratio of 0.26.
The current drug development process aims to produce safe, effective drugs within a reasonable time and at a reasonable cost. Phase II metabolism (glucuronidation) can affect drug action and pharmacokinetics to a considerable extent and so its studies and prediction at initial stages of drug development are very imperative. Extensive glucuronidation is an obstacle to oral bioavailability because the first-pass glucuronidation [or premature clearance by UDP-glucuronosyltransferases (UGTs)] of orally administered agents frequently results in poor oral bioavailability and lack of efficacy. Modeling of new chemical entities/drugs for UGTs and their kinetic data can be useful in understanding the binding patterns to be used in the design of better molecules. This review concentrates on first-pass glucuronidation by intestinal UGTs, including their topology, expression profile, and pharmacogenomics. In addition, recent advances are discussed with respect to substrate selectivity at the binding pocket, structural requirements, and mechanism of enzyme actions.
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