In silico-guided identification of potential inhibitors against β2m aggregation in dialysis-related amyloidosis

Abstract

In dialysis-related amyloidosis (DRA), misfolding of β2-microglobulin (β2m) leads to amyloid fibril deposition mainly in the skeletal joints seriously affecting their functionality. The identification and characterization of small-molecules that bind β2m and possibly inhibit its aggregation remain unexplored. In the present study, a ligand-based virtual screening approach and molecular dynamics (MD) simulations were employed to explore potent small-molecule inhibitors against β2m aggregation. The compounds were screened from various small-molecule databases by applying ligand-based virtual screening with rifamycin SV (RSV) as a reference compound. The molecular docking analysis was performed to filter out lead compounds with a higher binding affinity than RSV from a library of ∼800 compounds. Three compounds, ChEBI68321 (C1), ChEMBL360190 (C2) and ZINC3091144 (C3), displaying excellent binding free energies of –51.29, –36.51 and –34.36 kcal/mol, respectively, with β2m were subjected to MD simulations to get insights into the binding locations, key interactions and structural stability of the β2m-ligand complexes. The hydrogen bond analysis highlight higher structural stability and reduced flexibility of the loop regions of β2m in presence of C1, C2 and C3. The integrated computational approach employed in the present study identify promising lead compounds against β2m aggregation in DRA.Abbreviationsβ2mβ2-microglobulin3Dthree dimensionalADAlzheimer’s diseaseADTAutoDock ToolsDRADialysis-related amyloidosisDSSPdictionary of secondary structure of proteinsFELfree energy landscapeGROMACSGROningen MAchine for Chemical SimulationsLGALamarckian Genetic AlgorithmLINCSLINear Constraint SolverMCmain chainMDmolecular dynamicsMHC–Imajor histocompatibility complex class IMM–PBSAmolecular mechanics Poisson–Boltzmann surface areaPMEnanometer (nm); particle mesh ewaldPCAprincipal component analysisPDBprotein data bankRgradius–of–gyrationRSVrifamycin SVRMSDroot–mean–square deviationRMSFroot–mean–square fluctuationSCside chainSPCsimple point chargeSASASolvent accessible surface areaVMDvisual molecular dynamicsCommunicated by Ramaswamy H. Sarma