Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy.
Molecules. 2021 Aug 27;26(17):5208. doi: 10.3390/molecules26175208.
Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The -phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative , which has already been experimentally shown to inhibit thr with a K value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental K values, which were found equal to 0.058 and 6.95 μM for AChE and BChE, respectively. Thirty analogs of were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.
最近，直接凝血酶（thr）抑制剂达比加群已被证明对阿尔茨海默病（AD）的动物模型有益。为了发现针对 thr 和 AD 相关靶点的新型多模式试剂，通过 Multi-fingerprint Similarity Searching aLgorithm（MuSSeL）网络服务器对先前和新合成的强效 thr 和因子 Xa（fXa）抑制剂进行了虚拟筛选。-苯基-1-（吡啶-4-基）哌啶-4-甲酰胺衍生物 ，已通过实验证明可抑制 thr，其 K 值为 6 nM，已被 MuSSeL 的新版本标记为胆碱酯酶（ChE）同工型（乙酰胆碱酯酶和丁酰胆碱酯酶，AChE 和 BChE）以及 thr、fXa 和其他酶和受体的结合物。有趣的是，MuSSeL 平台预测 的抑制效力在低至亚微摩尔范围内，这通过实验 K 值得到了证实，AChE 和 BChE 的 K 值分别为 0.058 和 6.95 μM。然后，对 的 30 种类似物进行了 thr、fXa、AChE 和 BChE 抑制剂的测定，以增加我们对其结构-活性关系的了解，同时通过分子交叉对接筛选合理研究了负责针对靶酶的多种活性的分子决定因素。
