<i>In silico</i>-guided identification of potential inhibitors against β<sub>2</sub>m aggregation in Dialysis-related amyloidosis
Creators: name: Simranjeet Singh Narang
name: Suniba Shuaib
name: Goyal, Deepti
name: Bhupesh Goyal
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biophysics
subject: Biochemistry
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences

description: In dialysis-related amyloidosis (DRA), misfolding of β<sub>2</sub>-microglobulin (β<sub>2</sub>m) leads to amyloid fibril deposition mainly in the skeletal joints seriously affecting their functionality. The identification and characterization of small-molecules that bind β<sub>2</sub>m 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 β<sub>2</sub>m 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 (C<sub>1</sub>), ChEMBL360190 (C<sub>2</sub>), and ZINC3091144 (C<sub>3</sub>), displaying excellent binding free energies of –51.29, –36.51, and –34.36 kcal/mol, respectively, with β<sub>2</sub>m were subjected to MD simulations to get insights into the binding locations, key interactions and structural stability of the β<sub>2</sub>m-ligand complexes. The hydrogen bond analysis highlight higher structural stability and reduced flexibility of the loop regions of β<sub>2</sub>m in presence of C<sub>1</sub>, C<sub>2</sub>, and C<sub>3</sub>. The integrated computational approach employed in the present study identify promising lead compounds against β<sub>2</sub>m aggregation in DRA. A ligand-based virtual screening approach and molecular dynamics (MD) simulations were employed to explore potent small-molecule inhibitors against β<sub>2</sub>–microglobulin (β<sub>2</sub>m) 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 (C<sub>1</sub>), ChEMBL360190 (C<sub>2</sub>), and ZINC3091144 (C<sub>3</sub>), displaying excellent binding free energies of –51.29, –36.51, and –34.36 kcal/mol, respectively, with β<sub>2</sub>m were subjected to MD simulations to get insights into the binding locations, key interactions and structural stability of the β<sub>2</sub>m-ligand complexes. The integrated computational approach employed in the present study identify promising lead compounds against β<sub>2</sub>m aggregation in DRA.