The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

Alireza Mansouri,Akio Miyamoto,Hassan Hakimi,Mostafa Zakariazadeh,Rasoul Kowsar

doi:10.1038/s41598-022-04778-y

Abstract

The novel coronavirus disease (COVID-19) is currently a big concern around the world. Recent reports show that the disease severity and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. In addition, some steroid structures have been reported to affect coronavirus, SARS-CoV-2, function and activity. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). Viral main protease is essential for the replication of SARS-CoV-2. It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. Computational data showed that estradiol interacted more strongly with the main protease active site. In the presence of calcitriol, the binding energy of the spike protein to ACE2 was increased, and transferring Apo to Locked S conformer of spike trimer was facilitated. Together, the interaction between spike protein and ACE2 can be disrupted by calcitriol. Potential use of estradiol and calcitriol to reduce virus invasion and replication needs clinical investigation.

Highlights

The novel coronavirus disease (COVID-19) is currently a big concern around the world
The three-dimensional geometry of ligands with protease (Fig. 1A) or spike protein (Fig. 1C) complexes was obtained from the lowest energy docking coordinates
The minimum binding energy was obtained from docking simulations using the Vina docking algorithm of different steroids with coronavirus protease or spike protein

Summary

Introduction

The novel coronavirus disease (COVID-19) is currently a big concern around the world. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. The effect of vitamin D on the treatment of COVID-19 has been reported recently[23,24,25] These findings clearly indicate the potential role of steroids in the control of COVID-19 infection. Protease enzyme catalyzes proteolytic reactions by cleaving covalent chemical bonds into proteins It consists of three domains “I (residue 8–101), II (residue 102–184), and III (residue 201–306)” and one loop (residue 185–200: between domain I and II) in which the binding active site of protease located in the cleft between domain I and domain II. The first allosteric site is in dimerization domain that including Ile[213], Leu[253], Gln[256], Val[297] and Cys[300] from protomer A and Tyr[118], Asn[142] and Cys[145] from protomer B and the second is located in the cleft between main binding site (catalytic domain) and dimerization domain, including mainly these residues: Gln[110], Asp[153], Val[202], Ile[249], Pro[293], Phe[294], and A rg29842,43

Methods

Results

Discussion

Conclusion