Department of Pharmaceutical Chemistry, L.M.College of Pharmacy, Ahmedabad 380009, Gujarat, India.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India.
Curr Drug Discov Technol. 2020;17(2):233-247. doi: 10.2174/1570163815666181008165822.
Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators.
DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software.
Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.
药效团映射和分子对接可以协同集成，以改进药物设计和发现过程。已经描述了一种合理的策略，即组合药效团方法，源自结构和配体药效团的联合研究，用于鉴定新型 GPR40 调节剂。
使用 Discovery studio 中的 DISCOtech 模块生成基于结构和配体的药效团模型，这些模型给出了疏水性芳族、环芳族和负离子化作为必需药效团特征。通过筛选活性和非活性数据集、GH 评分和 ROC 曲线分析对生成的模型进行验证。最佳模型被暴露为 3D 查询，以从 GLASS（GPCR-配体关联）、GPCR SARfari 和 Mini-Maybridge 等数据库中筛选命中物。应用各种筛选条件来检索具有良好类药性的命中物分子。使用 SYBYL-X 1.2 软件对具有 TAK-875 作为配体复合物的 hGPR40（pdb：4PHU）的已知蛋白质结构进行分子对接研究。
对两个模型进行聚类，得到 RMSD 为 0.89。因此，本研究通过组合基于配体和结构的药效团模型，探索了最大特征。在 GPR40 调节中鉴定出的组合药效团中的一个共同结构基序包括对位取代的苯基丙酸支架。因此，组合药效团方法探索了最大的结构信息（来自配体和生物蛋白），最大程度地洞察了可能的蛋白-配体相互作用，并提供了潜在的先导候选物，如本研究所示。
