1. In search of small molecules blocking interactions between HIV proteins and intracellular cofactors
Katrien Busschots, Jan De Rijck, Frauke Christ and Zeger Debyser*. Mol. BioSyst., 2009, 5, 21–31
The standard therapy for HIV-1 infected patients (HAART) is based on cocktails of potent drugs targeting diﬀerent steps of the replication cycle. There are three main classes of drugs: protease inhibitors, nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Combinations of these drugs are given to minimise the risk of resistance development. Lately, novel drugs targeting other steps of the viral life cycle have entered the clinic and complement standard HAART therapy. Among these are Enfuvirtide (fusion inhibitor), Maraviroc (CCR5 entry inhibitor) and Raltegravir (integrase inhibitor).
2. Computational study on the interaction between CCR5 and HIV-1 entry inhibitor maraviroc: insight from accelerated molecular dynamics simulation and free energy calculation
Qifeng Bai, Yang Zhang, Xiaojun Yao*. Phys. Chem. Chem. Phys., 2014, 16, 24332—24338
To further understand the interaction mechanism between CCR5 and its inverse agonist, the details about the binding mode and dissociation process of Maraviroc in the pocket of CCR5 can provide much useful information. Molecular dynamics (MD) simulation can study the interaction mechanism between CCR5 and inverse agonist at the atomic level. Accelerated MD (aMD) simulations can provide an eﬀective way to search possible conformations of ligand in the pocket of CCR5. Hundreds of nanosecond aMD simulations are enough to capture millisecondtimescale events of unbiased MD simulations. For instance, some reports have proved that 100 ns aMD simulations can give the same simulation results as that obtained from more than 10 ms unbiased MD simulations based on the crystal structure of GPCRs. In the present work, both MD and aMD simulations are used to study the interaction mechanism between CCR5 and Maraviroc. Electrostatic potential analysis is also performed to study the possible escape pathway of Maraviroc in the binding pocket of CCR5. Free energy calculations are performed to profile the energetic change during the dissociation process ofMaraviroc. Our results can supply useful information to understand the interaction mechanism of Maraviroc in the pocket of CCR5 and to design a more potent inverse agonist of CCR5.