Abstract
Neuropathic pain and inflammatory pain are two common types of pathological pain in human health problems. To date, normal painkillers are only partially effective in treating such pain, leading to a tremendous demand to develop new chemical entities to combat pain and inflammation. A promising pharmacological treatment is to control signal transduction via the inflammatory mediator-coupled receptor protein C5aR by finding antagonists to inhibit C5aR activation. Here, we report the first computational study on the identification of non-peptide natural compound inhibitors for C5aR by homology modeling and virtual screening. Our study revealed a novel natural compound inhibitor Acteoside with better docking scores than all four existing non-peptidic natural compounds. The MM-GBSA binding free energy calculations confirmed that Acteoside has a decrease of ~39 kcal/mol in the free energy of binding compared to the strongest binding reference compound. Main contributions to the higher affinity of Acteoside to C5aR are the exceptionally strong lipophilic interaction, enhanced electrostatics and hydrogen bond interactions. Detailed analysis on the physiochemical properties of Acteoside suggests further directions in lead optimization. Taken together, our study proposes that Acteoside is a potential lead molecule targeting the C5aR allosteric site and provides helpful information for further experimental studies.Graphical
Highlights
Natural products derived from plants, fungi, bacteria, and marine organisms, which have long been utilized in Western and Eastern medicine, are widely investigated by modern science as ideal candidates for drug therapy
Our study revealed a novel natural compound inhibitor Acteoside with better docking scores than all four existing non-peptidic natural compounds
The Molecular Mechanics/GeneralizedBorn/Surface Area (MM-GBSA) binding free energy calculations confirmed that Acteoside has a decrease of *39 kcal/mol in the free energy of binding compared to the strongest binding reference compound
Summary
Natural products derived from plants, fungi, bacteria, and marine organisms, which have long been utilized in Western and Eastern medicine, are widely investigated by modern science as ideal candidates for drug therapy These natural products are usually secondary metabolites that can be metabolized by the human body and are promising alternatives to synthetic drugs (Butler, 2004). Based on recent results from several animal models for neuropathic pain, the G protein-coupled receptor C5aR has emerged as one of the potential pharmacological targets for treating neuropathic pain (Moriconi et al, 2014) As it is widely expressed in inflammatory cells, C5aR binds to anaphylatoxin C5a generated during complement system activation to result in an effective clearance of infectious agents (Gerard and Gerard, 1991). We generated the three-dimensional structure model of C5aR using comparative homology modeling and subsequently screening a library of approximately 1500 natural compounds toward the TM regions at the allosteric site of C5aR
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