Virtual Screening Of Inhibitors Against New Delhi Metallo-beta-lactamase-1

The "Superbugs" producing NDM-1 absorb widespreadly concerned around the world, because its plasmid gene bla NDM-1 can be spread quickly between the bacteria and all β-lactam antibiotics except that aztreonam can be hydrolyzed by NDM-1. As the "Superbugs" have a resistance to almost all antibiotics, human beings are facing with a serious health threat. It is currently a hot topic that NDM-1 inhibitors are screened to restore the efficacy of β-lactam antibiotics. But there is no drug approved by FDA targeted NDM-1, therefore, it is important to identify NDM-1 inhibitors with high activity and novel skeletons.The NDM-1 inhibitors screening process was established on the basis of constructing the NDM-1 inhibitors pharmacophore model. And the interaction of potentially active compounds was analysed by molecular dynamics simulation.First, 35 NDM-1 crystal protein were statistically analysed and two receptors-ligand binding modes were found. In mode A, there were two ligand groups coordinating with the two zinc ions and they constituted the quadrilateral. There was also a water coordinating with the two zinc ions. In mode B, there was only one ligand group coordinating with the two zinc ions and it occupied the position of the water between zinc ions, constituted a triangle with zinc ions. In addition, according to these two kinds of binding mode, two pharmacophore model were built—model A and model B.Then, a multistep virtual screening protocol was built and 2857595 compounds from Specs, Enamine and ChemDiv were screened. In the first step, 1409485 compounds were received by two parmacophore models. In the second step, 4998 compounds were obtained by docking. Finally, 51 potentially active compounds were gained based on knowledge.Finally, We simulated the interactions between 51 screened compounds and NDM-1 for 30 ns by molecular dynamic simulation technique. The results indicated that: 1) The coordination and electrostatic interaction of zinc ions played a major role in receptor-ligand binding. And the hydrogen bonds and the π-π conjugate are import interactions. 2) NDM-1 was easily combined when electric charge of ligand was-1. 3) In mode A, the modes of Zn1 interaction with compounds included coordination, strong electrostatic and weak electrostatic according to the distance.The research was meaningful for explaining the mechanism of NDM-1 inhibitors and exploring the new skeletons of NDM-1 inhibitors.