Rationalizing the activities of diverse cholecystokinin 2 receptor antagonists using molecular field points

Journal of Medicinal Chemistry
Caroline M R Low, Jeremy G Vinter

Abstract

Cholecystokinin 2 receptor antagonists encompass a wide range of structures. This makes them unsuitable candidates for existing 3D-QSAR methods and has led us to develop an alternative approach to account for their observed biological activities. A diverse set of 21 antagonists was subjected to a novel molecular field-based similarity analysis. The hypothesis is that compounds with similar field patterns will bind at the same target site regardless of their underlying structure. This initial report demonstrates a linear correlation between ligand similarity and biological activity for this challenging data set. A model generated with three molecules was used to predict the activity of 18 test compounds, with different chemotypes, with a root-mean-square error of 0.68 pKB units. The ability to automatically derive a molecular alignment without knowledge of the protein structure represents an improvement over existing pharmacophore methods and makes the method particularly suitable for scaffold-hopping.

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Citations

Feb 26, 2013·Chemical Reviews·Lukas WankaPeter R Schreiner
Dec 20, 2013·Journal of Medicinal Chemistry·Artem CherkasovAlexander Tropsha
Sep 21, 2015·Journal of Photochemistry and Photobiology. B, Biology·Noor E IramFarha Firdaus
Nov 5, 2015·Bioorganic & Medicinal Chemistry Letters·Marina TuyishimeSimon Cocklin
Sep 19, 2015·International Immunopharmacology·Igor A SchepetkinMark T Quinn
Jul 26, 2018·Breast Cancer Research and Treatment·Heba AlshakerDmitri Pchejetski
Nov 11, 2008·Journal of Chemical Information and Modeling·Timothy J CheeserightJeremy G Vinter

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