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Optimizing targeted inhibitors of P-glycoprotein using computational and structure guided approaches.

07:00 EST 8th November 2019 | BioPortfolio

Summary of "Optimizing targeted inhibitors of P-glycoprotein using computational and structure guided approaches."

Overexpression of ABC transporters like P-glycoprotein (P-gp) has been correlated with resistances in cancer chemotherapy. Intensive efforts to identify P-gp inhibitors for use in combination therapy have not led to clinically approved inhibitors to date. Here we describe computational approaches combined with structure-based design to improve the characteristics of a P-gp inhibitor previously identified by us. This hit compound represents a novel class of P-gp inhibitors that specifically targets and inhibits P-gp ATP hydrolysis, while not being transported by the pump. We describe here a new program for virtual chemical synthesis and computational assessment, ChemGen, to produce hit compound variants with improved binding characteristics. The chemical syntheses of several variants, efficacy in reversing multidrug resistance in cell culture and biochemical assessment of the inhibition mechanism are described. The usefulness of the computational predictions of binding characteristics of the inhibitor variants is discussed and compared to more traditional structure based approaches.

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This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
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Medical and Biotech [MESH] Definitions

A high affinity receptor for myelin-associated inhibitors (MAIs) that include NOGO-A PROTEIN; OLIGODENDROCYTE MYELIN GLYCOPROTEIN; and MYELIN-ASSOCIATED GLYCOPROTEIN. It is expressed primarily by neurons in the brain and OLFACTORY BULBS. During embryonic development, it is expressed in the PERIPHERAL NERVOUS SYSTEM. It localizes to GROWTH CONES and may inhibit neurite outgrowth following SPINAL INJURY.

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A 170-kDa transmembrane glycoprotein from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many ANTINEOPLASTIC AGENTS. Overexpression of this glycoprotein is associated with multidrug resistance (see DRUG RESISTANCE, MULTIPLE).

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Platelet membrane glycoprotein IIb is an integrin alpha subunit that heterodimerizes with INTEGRIN BETA3 to form PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX. It is synthesized as a single polypeptide chain which is then postranslationally cleaved and processed into two disulfide-linked subunits of approximately 18 and 110 kDa in size.

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