Dahiya Lalita, Mahapatra Manoj Kumar, Kaur Ramandeep, Kumar Vipin, Kumar Manoj
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014. India.
Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandar Sindri, Ajmer, Rajasthan- 305817. India.
Comb Chem High Throughput Screen. 2017;20(4):310-320. doi: 10.2174/1386207320666170315122459.
Metabolic disorders associated with diabetic patients are a serious concern. Aldose reductase (ALR2) has been identified as first rate-limiting enzyme in the polyol pathway which catalyzes the reduction of glucose to sorbitol. It represents one of the validated targets to develop potential new chemical entities for the prevention and subsequent progression of microvascular diabetic complications. In order to further understand the intricate structural prerequisites of molecules to act as ALR2 inhibitors, ligand-based pharmacophore model, atombased 3D-QSAR and structure based drug design studies have been performed on a series of 2,4- thiazolidinedione derivatives with ALR2 inhibitory activity.
In the present study, a validated six point pharmacophore model (AAADNR) with three hydrogen bond acceptor (A), one hydrogen bond donor (D), one negative ionic group (N) and one aromatic ring (R) was developed using PHASE module of Schrodinger suite with acceptable PLS statistics (survival score = 3.871, cross-validated correlation coefficient Q2 = 0.6902, correlation coefficient of multiple determination r2 = 0.9019, Pearson-R coefficient = 0.8354 and F distribution = 196.2). In silico predictive studies (pharmacophore modeling, atom-based 3D QSAR and docking combined with drug receptor binding free energetics and pharmacokinetic drug profile) highlighted some of the important structural features of thiazolidinedione analogs required for potential ALR2 inhibitory activity.
The result of these studies may account to design a legitimate template for rational drug design of novel, potent and promising ALR2 inhibitors.
糖尿病患者相关的代谢紊乱是一个严重问题。醛糖还原酶（ALR2）已被确定为多元醇途径中的首个限速酶，该酶催化葡萄糖还原为山梨醇。它是开发预防和后续延缓微血管糖尿病并发症潜在新化学实体的已验证靶点之一。为了进一步了解作为ALR2抑制剂的分子的复杂结构要求，已对一系列具有ALR2抑制活性的2,4-噻唑烷二酮衍生物进行了基于配体的药效团模型、基于原子的3D-QSAR和基于结构的药物设计研究。
在本研究中，使用薛定谔软件套件的PHASE模块开发了一个经过验证的六点药效团模型（AAADNR），该模型具有三个氢键受体（A）、一个氢键供体（D）、一个负离子基团（N）和一个芳香环（R），其PLS统计数据可接受（生存分数 = 3.871，交叉验证相关系数Q2 = 0.6902，多元决定系数r2 = 0.9019，皮尔逊R系数 = 0.8354，F分布 = 196.2）。计算机预测研究（药效团建模、基于原子的3D QSAR以及结合药物受体结合自由能和药代动力学药物概况的对接）突出了噻唑烷二酮类似物潜在ALR2抑制活性所需的一些重要结构特征。
这些研究结果可能有助于为新型、强效且有前景的ALR2抑制剂的合理药物设计设计一个合理的模板。
