An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor.

ABSTRACT: Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and (15)N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little se

SUBMITTER: Khattri RB 

PROVIDER: S-EPMC6274284 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature