Virtual drug screening study to discover novel ERAP1 allosteric site inhibitors for the treatment of ankylosing spondylitis (AS)

Abstract

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is one of the key molecules in the antigen presentation process. To date, associations of ERAP1 with Ankylosing Spondylitis (AS) have been revealed with strong data. As such, to target the allosteric site of ERAP1 exhibits a therapeutic potential in the treatment of AS. In this paper, 9,800 ligands from “FDA-Approved Drugs'', “World-not-FDA Approved Drugs'', and “Drugs in Clinical Trials'' datasets of ZINC15 database were screened to the allosteric site of ERAP1. The best scored drugs are filtered with ADME analysis, the toxicity and bioactivity profiles of the discovered drugs and the known inhibitors were investigated. Results revealed that ZINC000100052688 (Ventavis), ZINC000004217466, and ZINC000024760115 (Dactolicib) follow the Lipinski’s rule of five and have -10.0 kcal/mole, -9.8 kcal/mole, and -9.7 kcal/mole binding affinities to allosteric site of ERAP1, respectively. Furthermore, ZINC000004217466 is the most promising since it has high protease and enzyme inhibitory activity with no toxicity. Due to that to date, only few chemical ligands recognizing ERAP1 regulatory site have been synthesized, to reveal possible repurposable drugs is quite promising, and ZINC000004217466 is the best candidate among 9,800 drugs since it has rather binding affinity, proper chemical properties, no toxicity, and high bioactivity in the inhibition of ERAP1 regulatory site.

Keywords

• Ankylosing spondylitis
• Arthritis
• Autoimmunity
• ERAP1
• Virtual drug screening

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