Kulemina Lidia V, Ostrov David A
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
J Biomol Screen. 2011 Sep;16(8):878-85. doi: 10.1177/1087057111413919. Epub 2011 Aug 22.
The authors describe a structure-based strategy to identify therapeutically beneficial off-target effects by screening a chemical library of Food and Drug Administration (FDA)-approved small-molecule drugs matching pharmacophores defined for specific target proteins. They applied this strategy to angiotensin-converting enzyme 2 (ACE2), an enzyme that generates vasodilatory peptides and promotes protection from hypertension-associated cardiovascular disease. The conformation-based structural selection method by molecular docking using DOCK allowed them to identify a series of FDA-approved drugs that enhance catalytic efficiency of ACE2 in vitro. These data demonstrate that libraries of approved drugs can be rapidly screened to identify potential side effects due to interactions with specific proteins other than the intended targets.
作者描述了一种基于结构的策略，通过筛选美国食品药品监督管理局（FDA）批准的与特定靶蛋白定义的药效团匹配的小分子药物化学文库，来识别具有治疗益处的脱靶效应。他们将该策略应用于血管紧张素转换酶2（ACE2），这是一种产生血管舒张肽并促进预防高血压相关心血管疾病的酶。使用DOCK通过分子对接的基于构象的结构选择方法使他们能够鉴定出一系列在体外增强ACE2催化效率的FDA批准药物。这些数据表明，可以快速筛选批准药物文库，以识别由于与预期靶点以外的特定蛋白质相互作用而产生的潜在副作用。
