1st International and 10th National Iranian Conference on Bioinformatics
Home Accepted Papers
Repurposing of Latanoprost as an ADAM17 inhibitor: A ligand- and structure-based approach
Paper ID : 1470-ICB10
Authors:
Kourosh Daneshvarnejad *1, Homa Azizian2
1Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
2Department of Medicinal Chemistry, School of Pharmacy International Campus, Iran University of Medical Sciences, Tehran, Iran
Abstract:
Background: A disintegrin and metalloproteinase 17 (ADAM17), with its role in shedding various intercellular mediators, including tumor necrosis factor α (TNFα), has been considered a prominent drug target, particularly in inflammatory disorders and malignancies [1]. Despite efforts, no selective ADAM17 inhibitor has yet entered the pharmaceutical market due to systemic toxicities [2]. Drug repurposing seems to be a promising strategy for developing new ADAM17-based therapies. The current study aimed to identify FDA-approved drugs with the potential to be repurposed as selective ADAM17 inhibitors via a ligand- and structure-based approach.
Method: In this study, we screened the e-Drug3D database of FDA-approved drugs over the generated pharmacophore hypothesis AAADHR. All compounds that matched the hypothesis were screened over the ADAM17 crystallographic structure via a three-step Glide docking protocol. To identify ADAM17 selective inhibitors against matrix metalloproteinases (MMPs), we also docked the virtual screening hit compounds over the structures of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, MMP-14, and MMP-16. Among potential selective inhibitors, we selected the compound that formed the most stable complex with ADAM17 based on MM-GBSA free binding energy and molecular dynamics simulation findings.
Results: With a pharmacophore fitness score of 1.336 and an XP GScore of -9.838 in the ligand- and structure-based screening process, Latanoprost was identified as a possible inhibitor of ADAM17. Based on docking results over the MMPs structures (XP GScore > -9.17), this compound can selectively inhibit ADAM17. MM-GBSA ΔGBind of -38.30 and the average protein Cα RMSD value of 1.52±0.18 during the 120 ns MD simulation period confirm the stability of the Latanoprost-ADAM17 complex.
Conclusion: According to the results of this study and the Latanoprost pharmacokinetic properties, this drug has the potential to be a repurposing drug candidate, especially for inflammatory skin conditions.
Keywords:
ADAM17; Metalloproteinases; TNFα; Drug repurposing; Inflammation
Status : Paper Accepted (Poster Presentation)