Aim: The objects of this study originated from the experimental observations, whereby the HIV -1 gp120 V3 loop is a high-affinity ligand for immunophilins, and consisted in generating the structural complex of cycloph...Aim: The objects of this study originated from the experimental observations, whereby the HIV -1 gp120 V3 loop is a high-affinity ligand for immunophilins, and consisted in generating the structural complex of cyclophilin (Cyc) B belonging to immunophilins family with the virus subtype A V3 loop (SA-V3 loop) as well as in specifying the Cyc B segment forming the binding site for V3 synthetic copy of which, on the assumption of keeping the 3D peptide structure in the free state, may present a forwardlooking basic structure for anti-AIDS drug development. Methods: To reach the objects of view, molecular docking of the HIV-1 SA-V3 loop structure determined previously with the X-ray conformation of Cyc B was put into practice by Hex 4.5 program (http://www.loria.fr/~ritchied/ hex/) and the immunophilin stretch responsible for binding to V3 (Cyc B peptide) was identified followed by examination of its 3D structure and dynamic behavior in the unbound status. To design the Cyc B peptide, the X-ray conformation for the identical site of the native protein was involved in the calculations as a starting model to find its best energy structural variant. The search for this most preferable structure was carried out by consecutive use of the molecular mechanics and simulated annealing methods. The molecular dynamics computations were implemented for the Cyc B peptide by the GROMACS computer package (http:// www.gromacs.org/). Results: The overmolecular structure of Cyc B with V3 was built by computer modeling tools and the immunophilinderived peptide able to mask effectively the structurally invariant V3 segments embracing the functionally crucial amino acids of the HIV-1 gp120 envelope protein was constructed and analyzed. Conclusions: Starting from the joint analysis of the results derived with those of the literature, the generated peptide was suggested to offer a promising basic structure for making a reality of the protein engineering projects aimed at developing the anti-AIDS drugs able to stop the HIV’s spread.展开更多
近年来多巴胺D3受体(DRD_(3))在神经系统疾病的治疗过程中受到大量关注,包括帕金森、精神分裂、药物依赖等。本文综述2015年至今多巴胺D3受体选择性配体的研究进展,并以分子动力学原理为基础,利用Discovery Studio 4.5软件评价了这些配...近年来多巴胺D3受体(DRD_(3))在神经系统疾病的治疗过程中受到大量关注,包括帕金森、精神分裂、药物依赖等。本文综述2015年至今多巴胺D3受体选择性配体的研究进展,并以分子动力学原理为基础,利用Discovery Studio 4.5软件评价了这些配体的选择性,建立了基于分子共同特征的药效团模型,从类药分子库中筛选出对设计新型配体具有先导化合物意义的小分子化合物,以期对D3受体选择性配体的研究提供参考。展开更多
计算机辅助药物设计(Computer-Aided Drug Design,CADD)已成为当今药物研发不可或缺的一部分。采用传统的方法预测小分子结合自由能有一定的局限性,由于传统方法默认了小分子的结构信息与结合能之间是线性的关系,而对于结构-化学信息二...计算机辅助药物设计(Computer-Aided Drug Design,CADD)已成为当今药物研发不可或缺的一部分。采用传统的方法预测小分子结合自由能有一定的局限性,由于传统方法默认了小分子的结构信息与结合能之间是线性的关系,而对于结构-化学信息二者之间并不是线性关系的情况,其预测结果并不是十分准确。随着深度学习技术的发展,我们可以通过神经网络对线性问题或者是非线性问题进行建模,以在小分子的结构信息与其结合能之间建立线性或者非线性的联系,使其预测的结果准确率有所提高。展开更多
文摘Aim: The objects of this study originated from the experimental observations, whereby the HIV -1 gp120 V3 loop is a high-affinity ligand for immunophilins, and consisted in generating the structural complex of cyclophilin (Cyc) B belonging to immunophilins family with the virus subtype A V3 loop (SA-V3 loop) as well as in specifying the Cyc B segment forming the binding site for V3 synthetic copy of which, on the assumption of keeping the 3D peptide structure in the free state, may present a forwardlooking basic structure for anti-AIDS drug development. Methods: To reach the objects of view, molecular docking of the HIV-1 SA-V3 loop structure determined previously with the X-ray conformation of Cyc B was put into practice by Hex 4.5 program (http://www.loria.fr/~ritchied/ hex/) and the immunophilin stretch responsible for binding to V3 (Cyc B peptide) was identified followed by examination of its 3D structure and dynamic behavior in the unbound status. To design the Cyc B peptide, the X-ray conformation for the identical site of the native protein was involved in the calculations as a starting model to find its best energy structural variant. The search for this most preferable structure was carried out by consecutive use of the molecular mechanics and simulated annealing methods. The molecular dynamics computations were implemented for the Cyc B peptide by the GROMACS computer package (http:// www.gromacs.org/). Results: The overmolecular structure of Cyc B with V3 was built by computer modeling tools and the immunophilinderived peptide able to mask effectively the structurally invariant V3 segments embracing the functionally crucial amino acids of the HIV-1 gp120 envelope protein was constructed and analyzed. Conclusions: Starting from the joint analysis of the results derived with those of the literature, the generated peptide was suggested to offer a promising basic structure for making a reality of the protein engineering projects aimed at developing the anti-AIDS drugs able to stop the HIV’s spread.
基金This work was supported by the National Science and Technology Major Project(2022ZD0115003)the National Natural Science Foundation of China(No.92053202,No.92353304,No.22050003,No.21821004,No.21927901).
文摘近年来多巴胺D3受体(DRD_(3))在神经系统疾病的治疗过程中受到大量关注,包括帕金森、精神分裂、药物依赖等。本文综述2015年至今多巴胺D3受体选择性配体的研究进展,并以分子动力学原理为基础,利用Discovery Studio 4.5软件评价了这些配体的选择性,建立了基于分子共同特征的药效团模型,从类药分子库中筛选出对设计新型配体具有先导化合物意义的小分子化合物,以期对D3受体选择性配体的研究提供参考。
文摘计算机辅助药物设计(Computer-Aided Drug Design,CADD)已成为当今药物研发不可或缺的一部分。采用传统的方法预测小分子结合自由能有一定的局限性,由于传统方法默认了小分子的结构信息与结合能之间是线性的关系,而对于结构-化学信息二者之间并不是线性关系的情况,其预测结果并不是十分准确。随着深度学习技术的发展,我们可以通过神经网络对线性问题或者是非线性问题进行建模,以在小分子的结构信息与其结合能之间建立线性或者非线性的联系,使其预测的结果准确率有所提高。
