Histone Deacetylase Inhibitors as Potential COVID-19 Virus RNA-Dependent RNA Polymerase Inhibitors: A Molecular Docking and Dynamics Study

Research Article

Austin Crit Care J. 2021; 8(1): 1036.

Histone Deacetylase Inhibitors as Potential COVID-19 Virus RNA-Dependent RNA Polymerase Inhibitors: A Molecular Docking and Dynamics Study

Mohamed MFA1*, Sayed AM2, Abdelmohsen UR3,4, Nafady A5, Khashaba PY6,7, Hayallah AM8*

1Department of Pharmaceutical Chemistry, Sohag University, Sohag, Egypt

2Department of Pharmacognosy, Nahda University, Beni-Suef, Egypt

3Department of Pharmacognosy, Minia University, Minia, Egypt

4Department of Pharmacognosy, Deraya University, Minia, Egypt

5Department of Chemistry, King Saud University, Riyadh, Saudi Arabia

6Department of Pharmaceutical Analytical chemistry, Assiut University, Assiut, Egypt

7Department of Pharmaceutical Chemistry, Sphinx University, New Assiut City, Egypt

8Department of Pharmaceutical Organic Chemistry, Assiut University, Assiut, Egypt

*Corresponding author: Alaa M. Hayallah, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, New Assiut, Egypt, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt

Mamdouh F.A. Mohamed, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524- Sohag, Egypt

Received: March 30, 2021; Accepted: June 01, 2021; Published: June 08, 2021


The novel coronavirus disease that initially appeared in 2019, commonly identified as COVID-19 is an acute infectious disease precipitated by the SARSCoV- 2 and has become a severe pandemic health crisis. People stricken with a severe case of COVID-19 are subject to a relatively higher mortality rate, which is brought about predominantly by the difficulty of having potent and specific antiviral drugs for its treatment. In this context, the viral RNA-dependent RNA polymerase (RdRp) is an attractive target for antiviral inhibitors, mainly because of its essential role in processing the polyproteins translated from viral RNA. Moreover, histone deacetylases inhibitors represent one of the most promising antiviral agents. Therefore, in this contribution, the in silico structure-based drug design approach was employed to identify novel structural characteristics for the potential repurposed activity of HDACIs as antivirals against COVID-19. Herein, 12 HDAC inhibitors were screened to explore their potential anti-viral activity against RNA-dependent RNA polymerase (RdRp) (6NUR). Results revealed that large number of the screened HDAC inhibitors are strongly bound into the active binding site of crystallographic structure of RNA-dependent RNA polymerase (RdRp) (6NUR) with lowest CDOCKER energy and CDOCKER interaction energy are very close to those of the control drug remdesivir. Importantly, the virtually screened HDAC inhibitors, particularly, Givinostat, Pracinostat, Panobinostat, Romidepsin (FK228) and its active metabolite (RedF) could be promising candidates for COVID-19 RNA-dependent RNA polymerase (RdRp) inhibitors. Significantly, these inhibitors should be evaluated on their effectivity when treating COVID-19, specifically using the drugs that have been approved for clinical trials with limited toxicity.

Keywords: COVID-19; HDAC inhibitors; Repurposing strategy; SARSCoV- 2; Molecular docking; dynamics


Towards the end of year 2019, an unprecedented global outbreak of a newly identified coronavirus classified as severe acute respiratory syndrome (SARS-CoV-2), precipitated a global pandemic disease named COVID-19 [1–4]. The global health concerns have been elevated in recent times, due to the pandemic of (COVID-19) [5]. The extreme transmission rates and spread of disease have made the search for drug candidates to help in the reduction of this disease a global priority. A very successful strategy to combat a health crisis like this is drug repurposing, or more commonly recognized as repurposing or redirecting methods. Hence, drug redirecting of existing drugs is urgently required and could be a promising strategy for optimizing antiviral therapies that can successfully combat the SARS-CoV-2 infection in a short time. During the last few months, numerous FDA approved drugs and drugs under FDA examination have been repurposed for treating COVID-19 [6,7].

On the other hand, it is apparent that histone deacetylases inhibitors, in addition to their long history of use as targeted potent treatments for cancers [8,9], anti-epileptics, mood stabilizers [10]. antiparasitic [11] and anti-inflammatory [12], they have a potential role as novel therapeutic agents against viral infections [13]. The majority of HDAC inhibitors have three common pharmacophore patterns characterized as: A) Cap, B) linker, and C) Zinc Binding Group (ZBG) [14] as shown in Figure 1. Recently, six HDAC inhibitors (Figure 2) have been accepted as anticancer agents namely; Vorinostat (SAHA), [15] Romidepsin (FK228) and its active metabolite RedFK [16]. Belinostat (PXD101) [17], Pracinostat [18], Panobinostat (LBH-589) [19] and Chidamide (CS055) [20].