Open AccessDPP1 Inhibitors: Exploring the Role of Water in the S2 Pocket of DPP1 with Substituted Pyrrolidines
Author(s) -
Helena Käck,
Kevin Doyle,
Samantha Jane Hughes,
Michael S. Bodnarchuk,
Hans Lönn,
Amanda Van de Poël,
Norman D. Palmer
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00261
Subject(s) - nitrile , potency , pyrrolidine , chemistry , molecule , computational chemistry , stereochemistry , combinatorial chemistry , organic chemistry , biochemistry , in vitro
A series of pyrrolidine amino nitrile DPP1 inhibitors have been developed and characterized. The S2 pocket structure-activity relationship for these compounds shows significant gains in potency for DPP1 from interacting further with target residues and a network of water molecules in the binding pocket. Herein we describe the X-ray crystal structures of several of these compounds alongside an analysis of factors influencing the inhibitory potency toward DPP1 of which stabilization of the water network, demonstrated using Grand Canonical Monte Carlo simulations and free energy calculations, is attributed as a main factor.