Allosteric mechanism of an oximino-piperidino-piperidine antagonist for the CCR5 chemokine receptor.

The first step for the HIV-1 virus infecting host cell is bound with the CCR5 chemokine receptor. A set of allosteric inhibitors of oximino-piperidino-piperidine antagonists for CCR5 chemokine receptor was discovered. However, the allosteric mechanism of these inhibitors is still unsolved. Therefore, residue-level dynamics correlation network combining with on molecular dynamics simulation was used to investigate the allosteric mechanism. The dynamics correlation network of bound CCR5 is significantly different from that of free CCR5. The community of the most active complex suggests that the allosteric information can freely transfer from the allosteric site to the effector site of the second extracellular loop, while the information transfers bottleneck for the less active one. Here, a hypothesis was proposed that "binding-induced allosteric mechanism" was used to reveal the allosteric regulation of antagonists and the network perturbation confirmed it. Finally, the shortest path algorithm was used to identify the possible allosteric pathway with Gly173-Lys171-Thr177-Tyr89-LIG which was evaluated by the network perturbation of key residue. Furthermore, the efficiency of allostery for the most active system is the highest among these antagonist complexes. The strategy targeting the allosteric pathway can be used to design novel inhibitors of HIV-1 virus.