Abstract
Adenosine deaminases acting on RNA 1 (ADAR1) are enzymes involved in editing adenosine to inosine in the dsRNAs of cells associated with cancer development. The p150 isoform of ADAR1 is the only isoform containing the Za domain that binds to both Z-DNA and Z-RNA. The Za domain is suggested to modulate the immune response and could be a suitable target for antiviral treatment and cancer immunotherapy. In this study, we aimed to identify potential inhibitors for ADAR1 protein that bind the Za domain using molecular docking and simulation tools. Virtual docking and molecular dynamics simulation approaches were used to screen the potential activity of 2115 FDA-approved compounds on the Za domain of ADAR1 and filtered for to obtain the top-scoring hits. The top three compounds with the best XP Gscore-namely alendronate (-7.045), etidronate (-6.923), and zoledronate (-6.77)-were subjected to 50 ns simulations to characterize complex stability and identify the fundamental interactions that contribute to inhibition of the ADAR1 Za domain. The three compounds were shown to interact with Lys169, Lys170, Asn173, and Tyr177 of the Za domain-like helical backbone of Z-RNA. The study provides a comprehensive and novel insights of repurposes drugs for the inhibition of ADAR1 function. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).