In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 1149−1149
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COMPUTATIONAL STUDIES REVEAL STRUCTURAL FEATURES INFLUENCING ISOFORM SELECTIVITY OF CYP1 ENZYMES The design of isoform-selective inhibitors is relevant to the advancement of therapeutics and chemical tools. However, structural similarity among isoform binding sites and substrate preferences complicate this endeavor. In the present issue, Kim and colleagues (DOI: 10.1021/ acsmedchemlett.8b00409) disclose their work on determining isoform selectivity of the P450 subfamily CYP1, a group of enzymes linked to cancer. The three CYP1 family members exhibit a high degree of similarity in their overall structures and active site topologies. To elucidate isoform selectivity, the authors performed modifications of a previously discovered stilbenoid inhibitor and analyzed the resulting compounds via computational studies. This revealed the importance of hydrophobic interactions with certain phenylalanine residues of the enzyme. Furthermore, a thiophene analogue containing an imidazole moiety showed isoform preference. These results illustrate the application of a small adaptable ligand to isoform selectivity studies and could serve as a lead for the development of selective inhibitors.
late reductase mutants resistant to this inhibitor. Cocrystal structures of the inhibitors bound to the enzyme provided insights into the binding modes of these compounds that revealed simultaneous inhibition of both wild-type and mutant parasites. These results pave the way for further optimization studies with BT1 to obtain antifolates that can prevent the emergence of resistant mutants.
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OPTIMIZATION OF MYELOPEROXIDASE INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES Myeloperoxidase (MPO) is an enzyme involved in host defense mechanisms through production of reactive oxygen species. Overproduction of reactive oxygen species by MPO has been associated with tissue injury in various chronic inflammatory diseases. Small molecule MPO inhibitors may provide a treatment option; however, the number of effective compounds reported to date is limited. Herein, Wurtz et al. (DOI: 10.1021/acsmedchemlett.8b00308) report the optimization of a previously identified triazolopyridine MPO inhibitor that exhibited off-target activity toward another enzyme and acid instability. The authors designed and synthesized a series of triazolopyridine inhibitors via different synthetic routes, focusing on modifications of the benzyl ether moiety. Crystallographic data illustrated various binding modes of the compounds in the MPO active site, which guided optimization efforts. A thioether compound emerged as a potent MPO inhibitor in an acute mouse model of inflammation.
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HYBRID INHIBITORS THAT BIND TO BOTH WILD-TYPE AND MUTANT MALARIA PARASITES The emergence of parasite resistance increasingly threatens the fight against malaria. Of particular concern is the S108N mutation of the dihydrofolate reductase enzyme of Plasmodium falciparum, which causes steric clashing with rigid side chains of antifolate drugs, hence rendering these ineffective. Inhibitors with flexible side chains can evade this side chain interference and remain active against the mutant; however, additional mutations confer resistance to flexible inhibitors. Tarnchompoo et al. (DOI: 10.1021/acsmedchemlett.8b00389) addressed this problem by designing and synthesizing hybrid inhibitors that feature a rigid and flexible side chain at either end of the molecule. The authors discovered favorable IC50 and selectivity of the inhibitor BT1. Studies with a bacterial surrogate system to evaluate possible resistance mutations that could arise against BT1 showed limited diversity of Plasmodium falciparum dihydrofo© 2018 American Chemical Society
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Published: December 13, 2018 1149
DOI: 10.1021/acsmedchemlett.8b00560 ACS Med. Chem. Lett. 2018, 9, 1149−1149
