Structure‐Based Optimization of Aldose Reductase Inhibitors Originating from Virtual Screening
Structure‐Based Optimization of Aldose Reductase Inhibitors Originating from Virtual Screening
复制标题
基于虚拟筛选的醛糖还原酶抑制剂的结构优化
DOI：
10.1002/cmdc.200800410
复制
发表时间：
2009
期刊：
影响因子：
3.4
通讯作者：
M. Schlitzer
中科院分区：
文献类型：
--
作者：
M. Eisenmann;H. Steuber;M. Zentgraf;M. Altenkämper;R. Ortmann;J. Perruchon;G. Klebe;M. Schlitzer
虚拟筛选发现两个潜在的命中为潜在的线索，为醛糖还原酶抑制。基于它们与酶的晶体结构，进行了系统的优化，以揭示第一个结构-活性关系。中心噻吩部分和末端硝基具有最好的结合性质。糖尿病是一个普遍的健康问题。世界卫生组织（WHO）估计，2005年全世界有1.5亿人患有糖尿病。长期并发症是糖尿病治疗中的严重问题，表现为大血管和微血管并发症。山梨醇蓄积已被认为是微血管并发症（如肾病、神经病、视网膜病或白内障）发生的重要因素。醛糖还原酶（ALR 2）催化葡萄糖还原为山梨醇的NADPH依赖性还原，是预防这些并发症的重要靶点。新型醛糖还原酶抑制剂的开发预计将从基于结构的设计方法中受益匪浅。基于抑制剂IDD 594与人ALR 2复合物的高分辨晶体结构的虚拟筛选确定了两种化合物，其IC 50值在低微摩尔至亚微摩尔范围内。 基于配体与其结合口袋之间的已知相互作用，我们简化了先导结构以给出最小的结构要求，并从市售化合物开发了合成途径。测定新合成的化合物对ALR 2的抑制，显示出低至纳摩尔范围的抑制活性。我们系列中最有效的衍生物的晶体结构分析揭示了抑制剂结合模式的见解。
Virtual screeningdiscovered two prospective hits as potential leads for aldose reductase inhibition. Based on their crystal structures with the enzyme, a systematic optimization has been performed to reveal a first structure–activity relationship. A central thiophen moiety and a terminal nitro group exhibit the best binding properties.Diabetes mellitus is a universal health problem. The World Health Organization (WHO) estimates that 150 million people suffer from diabetes mellitus worldwide in 2005. Long‐term complications are a serious problem in the treatment of diabetes, manifesting in macrovascular and microvascular complications. Sorbitol accumulation has been proposed to be an important factor in the development of microvascular complications such as nephropathy, neuropathy, retinopathy or cataract. Catalyzing the NADPH‐dependent reduction of glucose to sorbitol, aldose reductase (ALR2) is an important target in the prevention of these complications. The development of novel aldose reductase inhibitors is expected to benefit strongly from a structure‐based design approach. A virtual screening based on the ultrahigh‐resolution crystal structure of the inhibitor IDD 594 in complex with human ALR2 identified two compounds with IC50values in the low micro‐ to submicromolar range. Based on the known interactions between the ligands and their binding pocket, we simplified the lead structures to give the minimal structural requirements and developed synthetic pathways from commercially available compounds. The newly synthesized compounds were assayed for their inhibition of ALR2, showing inhibitory activities down to the nanomolar range. Crystal structure analysis of the most potent derivative of our series revealed insights into the binding mode of the inhibitors.
登录
查看更多内容
Beiträge zum Studium der 噻唑，VIII。
DOI：
--
发表时间：
1964
期刊：
影响因子：
--
作者：
A. Silberg;A. Benkö;G. Csavassy
通讯作者：
G. Csavassy
人醛糖还原酶抑制剂的虚拟筛选
DOI：
10.1002/prot.20057
发表时间：
2004
期刊：
Proteins: Structure
影响因子：
--
作者：
O. Kraemer;I. Hazemann;A. Podjarny;G. Klebe
通讯作者：
G. Klebe
I. 2-芳基-4-卤甲基-噻唑的结构和特征
DOI：
--
发表时间：
1961
期刊：
影响因子：
--
作者：
A. Silberg;I. Simiti;H. Mantsch
通讯作者：
H. Mantsch
非硫醇法尼基转移酶抑制剂：N-(4-甲苯基乙酰氨基-3-苯甲酰基苯基)-3-芳基呋喃基丙烯酸酰胺。
影响因子：
3.5
作者：
A. Mitsch;P. Wissner;K. Silber;P. Haebel;I. Sattler;G. Klebe;M. Schlitzer
通讯作者：
M. Schlitzer
影响因子：
11.4
作者：
Bate, KL;Jerums, G
通讯作者：
Jerums, G