Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
Department of Pharmacy, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):819-830. doi: 10.1080/14756366.2021.1901088.
Compounds containg catechol or bisphosphonate were tested as inhibitors of the zinc metalloproteases, thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) which are bacterial virulence factors, and the human matrix metalloproteases MMP-9 and -14. Inhibition of virulence is a putative strategy in the development of antibacterial drugs, but the inhibitors should not interfere with human enzymes. Docking indicated that the inhibitors bound MMP-9 and MMP-14 with the phenyl, biphenyl, chlorophenyl, nitrophenyl or methoxyphenyl ringsystem in the S'-subpocket, while these ringsystems entered the S'- or S -subpockets or a region involving amino acids in the S'- and S'-subpockets of the bacterial enzymes. An arginine conserved among the bacterial enzymes seemed to hinder entrance deeply into the S'-subpocket. Only the bisphosphonate containing compound RC2 bound stronger to PLN and TLN than to MMP-9 and MMP-14. Docking indicated that the reason was that the conserved arginine (R203 in TLN and R198 in PLN) interacts with phosphate groups of RC2.
含儿茶酚或双膦酸盐的化合物被测试为锌金属蛋白酶的抑制剂，这些酶包括细菌毒力因子热稳定丝氨酸蛋白酶（TLN）、假丝氨酸蛋白酶（PLN）和金葡菌蛋白酶（ALN），以及人类基质金属蛋白酶 MMP-9 和 MMP-14。抑制毒力是开发抗菌药物的一种推测策略，但抑制剂不应干扰人类酶。对接表明，抑制剂与 MMP-9 和 MMP-14 结合，苯基、联苯基、氯苯基、硝基苯基或甲氧基苯基环系统位于 S'-亚口袋中，而这些环系统进入 S'-或 S-亚口袋或涉及细菌酶的 S'-和 S'-亚口袋中的氨基酸的区域。细菌酶中保守的精氨酸似乎阻碍了其深入进入 S'-亚口袋。只有含双膦酸盐的 RC2 化合物与 PLN 和 TLN 的结合比与 MMP-9 和 MMP-14 的结合更强。对接表明，原因是保守的精氨酸（TLN 中的 R203 和 PLN 中的 R198）与 RC2 的磷酸基团相互作用。
