Molecules, Vol. 29, Pages 1955: Ensemble-Based Virtual Screening Led to the Discovery of Novel Lead Molecules as Potential NMBAs

Molecules, Vol. 29, Pages 1955: Ensemble-Based Virtual Screening Led to the Discovery of Novel Lead Molecules as Potential NMBAs Molecules doi: 10.3390/molecules29091955 Authors: Yi Zhang Gonghui Ge Xiangyang Xu Jinhui Wu Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound d-tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs’ active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performe...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research