Computational Identification of Potential Isoflavonoid Derivatives Targeting SARS-CoV-2 Mpro and ACE2: Insights from Molecular Docking, DFT, and ADMET Analysis

Abstract

Background: The emergence of SARS-CoV-2 has highlighted the need for effective antiviral agents. The viral main protease (Mpro) and the host angiotensin-converting enzyme 2 (ACE2) are attractive therapeutic targets, involved in viral replication and entry, respectively. Objectives: To identify isoflavonoid derivatives with favorable predicted binding to SARS-CoV-2 Mpro and ACE2 using an integrated computational approach. Methods: Eighty-two naturally occurring isoflavonoid derivatives were evaluated using molecular docking, density functional theory (DFT) calculations, and in silico ADMET predictions. Results: Compounds 40, 50, 61, 66, 81, and 82 exhibited the most favorable predicted binding energies toward both Mpro and ACE2. Among these, the Ulexin C derivatives (compounds 81 and 82) achieved the most favorable docking scores under the applied computational protocol. DFT calculations supported their favorable electronic properties, and ADMET predictions indicated acceptable drug-likeness for all selected compounds, with no violations of Lipinski’s rule. Toxicity predictions suggested a medium risk of hERG inhibition for all selected compounds; additionally, compound 82 was predicted to be mutagenic in the Ames test, indicating a potential safety concern. Overall, compounds 50, 61, 66, and 81 were identified as the most promising candidates for further investigation. Conclusions: These findings identify several isoflavonoid derivatives, particularly Ulexin C-related compounds, as computationally prioritized candidates for further experimental evaluation against SARS-CoV-2. However, predicted binding affinities do not necessarily indicate inhibitory activity, and the computationally predicted toxicity profiles, particularly the mutagenicity of compound 82 and potential hERG liability, require experimental confirmation before further development.