Repurposing of Latanoprost as an ADAM۱۷ inhibitor: A ligand- and structure-based approach

Background: A disintegrin and metalloproteinase ۱۷ (ADAM۱۷), with its role in shedding variousintercellular mediators, including tumor necrosis factor α (TNFα), has been considered a prominent drugtarget, particularly in inflammatory disorders and malignancies. Despite efforts, no selective ADAM۱۷inhibitor has yet entered the pharmaceutical market due to systemic toxicities. Drug repurposing seems to bea promising strategy for developing new ADAM۱۷-based therapies. The current study aimed to identifyFDA-approved drugs with the potential to be repurposed as selective ADAM۱۷ inhibitors via a ligand- andstructure-based approach.Method: In this study, we screened the e-Drug۳D database of FDA-approved drugs over the generatedpharmacophore hypothesis AAADHR. All compounds that matched the hypothesis were screened over theADAM۱۷ crystallographic structure via a three-step Glide docking protocol. To identify ADAM۱۷ selectiveinhibitors against matrix metalloproteinases (MMPs), we also docked the virtual screening hit compoundsover the structures of MMP-۱, MMP-۲, MMP-۳, MMP-۷, MMP-۸, MMP-۹, MMP-۱۰, MMP-۱۲, MMP-۱۳,MMP-۱۴, and MMP-۱۶. Among potential selective inhibitors, we selected the compound that formed themost stable complex with ADAM۱۷ based on MM-GBSA free binding energy and molecular dynamicssimulation findings.Results: With a pharmacophore fitness score of ۱.۳۳۶ and an XP GScore of -۹.۸۳۸ in the ligand- andstructure-based screening process, Latanoprost was identified as a possible inhibitor of ADAM۱۷. Based ondocking results over the MMPs structures (XP GScore > -۹.۱۷), this compound can selectively inhibitADAM۱۷. MM-GBSA ΔGBind of -۳۸.۳۰ and the average protein Cα RMSD value of ۱.۵۲±۰.۱۸ during the۱۲۰ ns MD simulation period confirm the stability of the Latanoprost-ADAM۱۷ complex.Conclusion: According to the results of this study and the Latanoprost pharmacokinetic properties, this drughas the potential to be a repurposing drug candidate, especially for inflammatory skin conditions.

کلیدواژه ها:

ADAM۱۷ ، Metalloproteinases ، TNFα ، Drug repurposing ، Inflammation