亨廷顿病(HD)是一种罕见的进行性神经退行性疾病,由亨廷顿(HTT)基因的聚谷氨酰胺(poly-Q)突变引起,认知,和精神机能障碍.作为单基因条件,降低突变的亨廷顿蛋白(mHTT)的水平有望成为一种有效的治疗方法。GPR52,一种孤儿G蛋白偶联受体(GPCR),富含纹状体,是通过降低mHTT水平来减缓HD进展的新目标。因此,该研究的重点是结合稳健的高通量虚拟筛选(HTVS)和药代动力学分析,然后进行快速提取配体(FPL)和伞形采样(US)模拟,确定GPR52的有效小分子抑制剂.最初,针对GPR52的结合袋进行2,36,545种化合物的文库的筛选。基于结合亲和力,立体化学和非键合相互作用,和药代动力学分析,50个化合物入围。对所选择的命中化合物1、2和3进行FPL模拟,其中施加外部偏压电位以研究其独特的解离途径和随时间的分子间相互作用。随后,在选定的命中化合物上进行US模拟以估计它们的结合自由能(ΔG)。对从模拟中获得的轨迹的分析表明,GPR52活性位点内的残基TYR34,TYR185,GLY187,ASP188,ILE189,SER299,PHE300和THR303对于通过形成各种氢键相互作用和疏水接触的有效配体结合具有重要意义。在三个热门化合物中,化合物3的最低ΔG为-20.82±0.44kcal/mol。该研究将化合物1、2和3确定为潜在分子,可作为GPR52抑制剂开发,有望降低mHTT水平。
Huntington\'s disease (HD) is a rare and progressive neurodegenerative disorder caused by polyglutamine (poly-Q) mutations of the huntingtin (HTT) gene resulting in chorea, cognitive, and psychiatric dysfunctions. Being a monogenic condition, reducing the levels of the mutated huntingtin protein (mHTT) holds promise as an effective therapeutic approach. GPR52, an orphan G-protein coupled receptor (GPCR), enriched in the striatum, is a novel target for slowing down the progression of HD by lowering the mHTT levels. Therefore, the study focuses on identifying potent small-molecule inhibitors for GPR52 using a combination of robust high-throughput virtual screening (HTVS) and pharmacokinetics profiling followed by fast pulling of ligand (FPL) and umbrella sampling (US) simulations. Initially, screening a library of 2,36,545 compounds was done against the binding pocket of GPR52. Based on binding affinity, stereochemical and non-bonded interactions, and pharmacokinetic profiling, 50 compounds were shortlisted. Selected hit compounds 1, 2, and 3 were subjected to FPL simulations with applied external bias potential to investigate their unique dissociation pathways and intermolecular interactions over time. Subsequently, the US simulations were performed on the selected hit compounds to estimate their binding free energy (ΔG). The analysis of the trajectories obtained from simulations revealed that the residues TYR34, TYR185, GLY187, ASP188, ILE189, SER299, PHE300, and THR303 within the active site of GPR52 were significant for efficient ligand binding through the formation of various hydrogen bond interactions and hydrophobic contacts. Out of the three hit compounds, compound 3 had the lowest ΔG of - 20.82 ± 0.44 kcal/mol. The study identified compounds 1, 2, and 3 as potential molecules that can be developed as GPR52 inhibitors holding promise for lowering mHTT levels.