Targeting GPR52 for potential agonists for schizophrenia therapy: A computational drug discovery study

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling Pub Date : 2025-02-21 DOI:10.1016/j.jmgm.2025.108994

Selinay Demir, Güzin Tunca Alparslan

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Abstract

G Protein-Coupled Receptors (GPCRs) are one of the most attractive therapeutic targets due to their active role in different systems and disease types. The increasing three-dimensional structure information of GPCRs has made them interesting for Structure-Based Drug Design (SBDD) studies. There are various orphan GPCRs whose endogenous molecules have not yet been identified, although their structural information is known. The recent discovery of the three-dimensional structure of GPR52, an orphan GPCR involved in central nervous system diseases, made it stand out as a drug target. In this study, it is aimed to find a lead drug molecule candidate for GPR52 by using structure-based drug design techniques. The study comprises a set of SBDD methods, including preparation of a small molecule library, pharmacophore modeling, molecular docking, consensus scoring, molecular dynamics simulations, calculation of binding free energy, and in silico pharmacokinetic studies for GPR52. It is expected that the molecules obtained as a result of the study may be strong candidates for in vitro and in vivo experiments or could be used as lead drug molecules in new drug discovery and development studies.

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以 GPR52 为靶点，寻找治疗精神分裂症的潜在激动剂：计算药物发现研究

G蛋白偶联受体（gpcr）由于其在不同系统和疾病类型中的积极作用而成为最具吸引力的治疗靶点之一。越来越多的gpcr三维结构信息使它们成为基于结构的药物设计（SBDD）研究的兴趣。有各种孤儿gpcr，其内源性分子尚未被鉴定，尽管它们的结构信息是已知的。GPR52是一种参与中枢神经系统疾病的孤儿GPCR，最近发现了它的三维结构，使它成为一个突出的药物靶点。本研究旨在利用基于结构的药物设计技术寻找GPR52的先导药物候选分子。本研究包括一套SBDD方法，包括制备小分子文库、药效团建模、分子对接、共识评分、分子动力学模拟、结合自由能计算、GPR52的计算机药代动力学研究。预计该研究获得的分子可能是体外和体内实验的有力候选者，或可作为新药发现和开发研究的先导药物分子。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of molecular graphics & modelling 生物-计算机：跨学科应用

CiteScore

5.50

自引率

6.90%

发文量

216

审稿时长

35 days

期刊介绍： The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design. As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.