Exploring epigenetic drugs as potential inhibitors of SARS-CoV-2 main protease: a docking and MD simulation study

Uzuner U., Akkus E., Kocak A., Çelik Uzuner S.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Publication Date: 2023
  • Doi Number: 10.1080/07391102.2023.2236714
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core
  • Keywords: binding free energy, COVID-19, docking, drug repurposing, epigenetics, main protease, molecular dynamics, SARS-CoV-2
  • Karadeniz Technical University Affiliated: Yes


The COVID-19 pandemic has caused havoc around the globe since 2019 and is considered the largest global epidemic of the twentieth century. Although the first antiviral drug, Remdesivir, was initially introduced against COVID-19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection. FDA-approved Paxlovid (Nirmatrelvir supplemented by Ritonavir) was recently announced as a promising drug against the SARS-CoV-2 major protease (M-pro). Here we report for the first time the remarkable inhibitory potentials of lead epigenetic-targeting drugs (epi-drugs) against SARS-CoV-2 M-pro. Epi-drugs are promising compounds to be used in combination with cancer chemotherapeutics to regulate gene expression. The search for all known epi-drugs for the specific inhibition of SARS-CoV-2 M-pro was performed for the first time by consensus (three high-order program) molecular docking studies and end-state free energy calculations. Several epi-drugs were identified with highly comparable binding affinity to SARS-CoV-2 M-pro compared to Nirmatrelvir. In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 M-pro. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-M-pro complex with MM-GBSA binding free energy (& UDelta;G(bind)) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma