Allosteric Mechanism of Cyclopropylindolobenzazepine Inhibitors for HCV NS5B RdRp via Dynamic Correlation Network

作     者：Mueed Ur Rahman 

作者单位：上海交通大学 

学位级别：硕士

导师姓名：陈海峰

授予年度：2017年

学科分类：100702[医学-药剂学] 1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100602[医学-中西医结合临床] 10[医学] 

摘      要：Inhibitor induced allosteric regulation is associated with signaling event a protein generate through inhibitor binding and transmitted to a second site via long-range intra-molecular communication that causes a change in the structural conformation at a distal site and leads to a change in function（*** efficiency or binding affinity）,likewisethe cellular protein allosteric regulation that respond to changes in concentrations of small *** the same phenomena of cellular protein regulation,Compound M2,a cyclopropylindolobenzazepine derivative among the HCV RNA dependent RNA polymerase（RdRp）nonstructural protein 5B（NS5B）targeted drugs,bind to site 1 of thumb domain distant from catalytic site and allosterically inhibit HCV NS5 B RdRp activity prior to *** vitro and crystallographic studies evidenced the potency of inhibitory activity and structural changes the M2 and similar inhibitors produced in HCV NS5 B at distal ***,the experimental methods are not enough to explain the detailed allosteric mechanism for these derivatives and similar inhibitors at molecular *** continuous improvements in field of computations,molecular dynamics simulations along with algorithm design are likely to play an increasingly important role to overcome such *** this study fluctuation correlation networks were constructed based on all-atom molecular dynamics simulations to elucidate the allosteric mechanism of M2 bound to NS5 *** fluctuation correlation networks between free and M2 bound NS5 B are significantly *** information can better transfer from the allosteric site to the catalytic site for bound NS5 B than for free NS5 ***,the hypothesis of “binding induced allosteric regulation is proposed to link the enzyme inactivation and inhibitor binding and then confirmed by mutant ***,one possible allosteric pathway was identified with the shortest path and evaluated by the perturbation of the network.