Joseph-McCarthy D, Hogle J M, Karplus M
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Proteins. 1997 Sep;29(1):32-58. doi: 10.1002/(sici)1097-0134(199709)29:1<32::aid-prot3>3.0.co;2-h.
A combinatorial ligand design approach based on the multiple copy simultaneous search (MCSS) method and a simple scheme for joining MCSS functional group sites was applied to the binding pocket of P3/Sabin poliovirus and rhinovirus 14. The MCSS method determines where specific functional (chemical) groups have local potential energy minima in the binding site. Before the virus application, test calculations were run to determine the optimal set of input parameters to be used in evaluating the MCSS results. The MCSS minima are analysed and selected minima are connected with (CH2)n linkers to form candidate ligands, whose structures are optimized in the binding site. Estimates of the binding strength were made for the ligands and compared with those for known drugs. The results indicate that the proposed ligands should bind to P3/Sabin poliovirus at least as well as the best of the existing drugs, and that they should also bind to P1/Mahoney poliovirus and rhinovirus 14. A detailed comparison of the poliovirus and rhinovirus binding pockets and an analysis of drug binding specificity is presented.
一种基于多重复本同时搜索（MCSS）方法和连接MCSS官能团位点的简单方案的组合配体设计方法，被应用于P3/萨宾脊髓灰质炎病毒和鼻病毒14的结合口袋。MCSS方法确定特定官能（化学）基团在结合位点何处具有局部势能最小值。在应用于病毒之前，进行了测试计算以确定用于评估MCSS结果的最佳输入参数集。对MCSS最小值进行分析，并将选定的最小值与(CH2)n连接子相连以形成候选配体，其结构在结合位点进行优化。对配体的结合强度进行了估计，并与已知药物的结合强度进行了比较。结果表明，所提出的配体与P3/萨宾脊髓灰质炎病毒的结合至少应与现有最佳药物一样好，并且它们也应与P1/马奥尼脊髓灰质炎病毒和鼻病毒14结合。本文给出了脊髓灰质炎病毒和鼻病毒结合口袋的详细比较以及药物结合特异性分析。
