...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >Pharmacophore Fragment-Based Prediction and Gas-Phase ab Initio Optimization of Carvedilol Conformations
【24h】

Pharmacophore Fragment-Based Prediction and Gas-Phase ab Initio Optimization of Carvedilol Conformations

机译：卡夫地洛构象的基于药理学片段的预测和气相从头算优化

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

This current communication gives the results of a novel computational molecular method of selecting,from a vast number of possible conformations,the dominant low-energy states of a large molecule by dividing it into separately analyzable structure-activity fragments.Carvedilol is a cardiovascular drug of proven efficacy with multiple molecular targets:it acts as a nonselective beta-adrenoceptor(beta_1 and beta_2)and selective alpha_1-adrenoceptor antagonist,an antioxidant able to reduce reactive oxygen species(ROS)-mediated oxidative stress,a beneficial modulator of cardiac electrophysiological properties(K~+and Ca~2+ion channels),a multifaceted cardioprotector,and novel antifibrillar agent able to inhibit amyloid-beta(Abeta)fibril formation.Given carvedilol's varied pharmacodynamic profiles,and the fact that a thorough analysis of its potential energy hypersurface(PEHS)has not yet been performed,an original molecular fragmentation method was developed to reveal carvedilol's low-energy states,to divulge their relevance to its biological activity.Multidimensional conformational analysis(MDCA)leads to a total of 177 147(3~11)conformational possibilities,whereas fragmentation studies predict 240 gas-phase conformations.Structural predictions were tested on protonated beta-carvedilol with gas-phase molecular orbital(MO)computations of PEHS minima at the restricted Hartree-Fock(RHF)(RHF/3-21G)level of theory,using the Gaussian 98 software program.Computation of the 240 predicted(input)carvedilol conformations revealed 121 converged(i.e.,fully optimized)structures,of which nine possessed a conformer relative energy of <4 kcal/mol.Seven of these nine conformers possess a unique "tetra-centric"(four-centered)spiro-type structure that is composed of two rings(six-and eight-membered)enclosed by two O...H-N hydrogen bonds(H-bonds)that are connected via the protonated N atom in the side chain of carvedilol;this conformation is largely determined by the carbazole-containing pharmacophore(Fragment A)of carvedilol.In regard to the utility of the rational molecular fragmentation method used to predict and optimize the carvedilol structures,it is determined that 8 of the 11 torsional angles were accurately predicted(72.7%),according to torsional angle conformation distribution.The strength of this fragmentation method relies on full MDCA optimization of the individual fragments,which are then used to predict the carvedilol conformations.As such,the predicted inputs possess an inherent degree of energy minimization and,thus,are able to provide a better hypothesis of relevant sections of the carvedilol surface versus a random sampling of the PEHS.The elucidation of carvedilol's conformational identity greatly aids the full molecular understanding of carvedilol's adrenoceptor binding structure and carvedilol's involvement,at the molecular level,in ameliorating pathological states such as oxidative stress and Alzheimer's disease.
机译：当前的交流给出了一种新颖的计算分子方法的结果，该方法从大量可能的构象中将大分子划分为可单独分析的结构活性片段，从而选择了大分子的主要低能态。卡维地洛是一种心血管药物经过验证的具有多种分子靶标的功效：它可作为非选择性β-肾上腺素受体（β_1和β_2）和选择性α_1-肾上腺素受体拮抗剂，一种能够减少活性氧（ROS）介导的氧化应激的抗氧化剂，是心脏电生理特性的有益调节剂（K〜+和Ca〜2 +离子通道），多方面的心脏保护剂和能够抑制β-淀粉样蛋白（Abeta）原纤维形成的新型抗原纤维剂。鉴于卡维地洛具有多种药效学特征，并且对其潜在能量进行了全面分析超表面（PEHS）尚未进行，开发了一种原始的分子裂解方法来揭示卡维地洛的低能多维构象分析（MDCA）导致总共177 147（3〜11）构象可能性，而片段化研究预测了240个气相构象。使用高斯98软件程序在严格的Hartree-Fock（RHF）（RHF / 3-21G）理论水平上以PEHS极小分子的气相分子轨道（MO）计算的卡维地洛。使用240个预测的（输入）卡维地洛进行计算构象揭示了121个会聚（即完全优化）的结构，其中9个构象异构体相对能量<4 kcal / mol。这9个构象异构体中的7个具有独特的“四中心”（四中心）螺型结构，由两个环（六元和八元）环组成，两个环被卡维地洛侧链中的质子化N原子连接的两个O ... HN氢键（H键）包围;这种构象主要取决于含咔唑的药卡维地洛的Macophore（片段A）。考虑到合理的分子断裂方法可用于预测和优化卡维地洛的结构，确定准确预测了11个扭转角中的8个（72.7％），根据扭转角这种碎裂方法的强度取决于单个碎片的完整MDCA优化，然后用于预测卡维地洛的构象。因此，预测的输入具有固有的能量最小化程度，因此能够提供卡维地洛表面相关部分的假设比PEHS的随机取样更好。阐明卡维地洛的构象同一性极大地帮助了卡维地洛的肾上腺素受体结合结构的分子全面了解以及卡维地洛在分子水平上参与改善病理状态如氧化应激和阿尔茨海默氏病。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号