Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Chem Inf Model. 2011 Feb 28;51(2):315-25. doi: 10.1021/ci100402f. Epub 2011 Jan 24.
A 5-HT(2A) receptor model was constructed by homology modeling based on the β(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(αq) peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT(2A) receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.
基于β(2)-肾上腺素能受体和 G 蛋白结合视蛋白晶体结构，通过同源建模构建了 5-HT(2A) 受体模型。通过激动剂配体和 G(αq) 肽在随后的四个定向分子动力学 (MD) 模拟中，将 5-HT(2A) 受体模型转换为活性构象。转化的驱动力是添加几个已知的分子间和受体螺旋间氢键，强制进行必要的螺旋和构象转变运动。随后的无约束 MD 模拟证实了激活的受体模型的稳定性，并揭示了有关稳定残基和键的新信息。通过对超过 9400 种化合物（其中 182 种为已知配体）的回顾性配体筛选进一步验证了活性 5-HT(2A) 受体模型。结果表明，该模型可用于药物发现中的虚拟筛选和基于结构的配体设计，以及 GPCR 激活研究。
