Abstract
BACKGROUND AND PURPOSE: A genome-wide clustered regularly interspaced short palindromic repeats- associated protein 9-based screen has revealed that the cell adhesion molecule matrix remodelling associated protein 8 (Mxra8) acts as an entry mediator for many alphaviruses including chikungunya virus. The first X-ray crystal structure reported for Mxra8 a few months ago has a low-resolution of 3.49Å. EXPERIMENTAL APPROACH: Homology modelling of Mxra8 protein was done employing the SWISS-MODEL and PRIME module of Maestro. To design novel Mxra8 inhibitors pharmacophore guided fragment-based drug design and structure-based virtual screening of Food and Drug Administration approved drug libraries were undertaken. Molecular docking and molecular dynamics (MD) simulations study were carried out to validate the findings. FINDINGS / RESULTS: The molecule H1a (dock score: -6.137, binding energy: -48.95 kcal/mol, and PHASE screen score: 1.528816) was identified as the best hit among the fragment-based designed ligands. Structure- based virtual screening suggested histamine, epinephrine, and capreomycin as potential hits which could be repurposed as Mxra8 inhibitor. MD simulations study suggested that only small molecules like histamine could be a potential inhibitor of Mxra8. H-bond interaction with Arg58 and Glu200 amino acid residues seems to be crucial for effective binding. CONCLUSION AND IMPLICATIONS: To the best of our knowledge, this is the first report on the design of novel inhibitors against Mxra8 protein to tackle the menace of alphaviruses infections. This design strategy could be used for structure-based drug design against other apo-proteins. This study also advances the application of in silico tools in the field of drug repurposing.