Fortuitous In Vitro Compound Degradation Produces a Tractable Hit against Mycobacterium tuberculosis Dethiobiotin Synthetase: A Cautionary Tale of What Goes In Does Not Always Come Out.
ACS chemical biology(2023)
摘要
We previously reported potent ligands and inhibitors of dethiobiotin synthetase (DTBS), a promising target for antituberculosis drug development (Schumann et al., . 2021, , 2339-2347); here, the unconventional origin of the fragment compound they were derived from is described for the first time. Compound (9b-hydroxy-6b,7,8,9,9a,9b-hexahydrocyclopenta[3,4]cyclobuta[1,2-]chromen-6(6aH)-one), identified by an fragment screen, was subsequently shown by surface plasmon resonance to have dose-responsive binding ( = 0.6 mM). Clear electron density was revealed in the DAPA substrate binding pocket when was soaked into DTBS crystals, but the density was inconsistent with the structure of . Here, we show that the lactone of hydrolyzes to a carboxylic acid () under basic conditions, including those of the crystallography soak, with a subsequent ring opening of the component cyclobutane ring forming a cyclopentylacetic acid (). Crystals soaked directly with authentic produced an electron density that matched that of crystals soaked with presumed , confirming the identity of the bound ligand. The synthetic utility of fortuitously formed enabled the subsequent compound development of nanomolar inhibitors. Our findings represent an example of chemical modification within drug discovery assays and demonstrate the value of high-resolution structural data in the fragment hit validation process.
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