Das Sucharita, Chakraborty Sandipan, Basu Soumalee
Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India.
Cent Nerv Syst Agents Med Chem. 2015;15(1):52-64. doi: 10.2174/1871524915666150127122546.
BACE1, the aspartate protease that generates amyloid-β peptide (Aβ) in the brain of AD (Alzheimer's disease) patients, has emerged as a pharmaceutically relevant target. Here, a fragment-based in silico approach has been adopted to design novel compounds with increased ligand efficiency for BACE1, before screening for brain permeability and toxicity. Fragments docked to the active site of BACE1 and sorted into two groups using binding energy cut-off, were joined to create novel ligands with binding energy lying in the range between -11.36 kcal/mol and -8.56 kcal/mol. Interestingly, QIN, a known inhibitor of BACE1 with an IC50 of 11nM, when docked to BACE1, shows a binding energy (-9.43 kcal/mol) lying within the range of the novel ligand-BACE1 complexes. The present strategy thus enabled the design of four novel inhibitors of BACE1 with favourable binding energy, brain permeability and no toxicity that might show promise as leads in future.
β-分泌酶1（BACE1）是一种天冬氨酸蛋白酶，可在阿尔茨海默病（AD）患者大脑中生成β淀粉样肽（Aβ），已成为一个具有药物研发意义的靶点。在此，我们采用基于片段的计算机辅助方法，在筛选脑通透性和毒性之前，设计出对BACE1具有更高配体效率的新型化合物。对接至BACE1活性位点并使用结合能截止值分为两组的片段，被连接起来以创建结合能在-11.36千卡/摩尔至-8.56千卡/摩尔范围内的新型配体。有趣的是，已知的BACE1抑制剂QIN，其IC50为11nM，对接至BACE1时，显示出的结合能（-9.43千卡/摩尔）处于新型配体 - BACE1复合物的能量范围内。因此，本策略能够设计出四种对BACE1具有良好结合能、脑通透性且无毒性的新型抑制剂，这些抑制剂未来可能有望成为先导化合物。
