Ara Ayami, Kadoya Ryushi, Ishimura Hiromi, Shimamura Kanako, Sylte Ingebrigt, Kurita Noriyuki
Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi, 441-8580, Japan.
Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway.
J Mol Graph Model. 2017 Aug;75:277-286. doi: 10.1016/j.jmgm.2017.05.013. Epub 2017 Jun 8.
Bacteria secrete the enzyme pseudolysin (PLN) to degrade exocellular proteins, and the produced peptides are used as a nutrient for the bacteria. It is thus expected that inhibition of PLN can suppress bacterial growth. Since such inhibitors do not attack to bacteria directly, the risk of producing drug-resistance bacteria is less. However, endogenous proteinases such as the matrix metalloproteinases (MMPs) have active site similar to that of PLN, and there is a possibility that PLN inhibitors also inhibit the activity of MMPs, resulting in a loss of substrate degradation by these proteinases. Therefore, agents that inhibit the activity of only PLN and not MMPs are required. In the present study, we select two compounds (ARP101 and LM2) and investigate their specific interactions with PLN and MMPs by use of ab initio molecular simulations. Based on the results, we propose several novel compounds as candidates for potent PLN inhibition and investigate their binding properties with PLN, elucidating that the compound, in which a toluene group is introduced into LM2, has larger binding energy with PLN compared with the pristine LM2. Therefore, this compound is suggested to be a potent PLN inhibitor.
细菌分泌假溶素（PLN）酶来降解细胞外蛋白质，产生的肽被用作细菌的营养物质。因此，预计抑制PLN可以抑制细菌生长。由于此类抑制剂不直接攻击细菌，产生耐药菌的风险较小。然而，内源性蛋白酶如基质金属蛋白酶（MMPs）具有与PLN相似的活性位点，PLN抑制剂有可能也抑制MMPs的活性，导致这些蛋白酶失去底物降解能力。因此，需要仅抑制PLN活性而不抑制MMPs的药物。在本研究中，我们选择了两种化合物（ARP101和LM2），并通过从头算分子模拟研究它们与PLN和MMPs的特异性相互作用。基于这些结果，我们提出了几种新型化合物作为强效PLN抑制剂的候选物，并研究它们与PLN的结合特性，阐明了在LM2中引入甲苯基团的化合物与原始LM2相比，与PLN具有更大的结合能。因此，该化合物被认为是一种强效的PLN抑制剂。
