Computational Investigation of Vitamin D3 and its Hydroxyderivatives as Promising Drugs against COVID-19

COVID-19 pandemic caused by SARS-CoV-2 presents a great threat to public health. One important epidemiologic correlation with SARS-CoV-2 infection is the prevalence of vitamin D deficiency patients with severe COVID-19 symptoms. This observation is not limited to a region or a particular type of population, instead is noticeable worldwide. The geographical regions with less sunlight and reported vitamin D deficiency show high mortality rate. Vitamin D3 belongs to a group of fat-soluble secosteroids, which after enzymatic activation plays a central role in intestinal absorption of calcium, magnesium, and phosphate and controls the expression of roughly 5% of human genes, and regulates cell proliferation and differentiation, immune-regulation, interaction with viral factors, autophagy and apoptosis. Biologically active vitamin D3 hydroxyderivative 1,25(OH)2D3 regulates calcium body homeostasis and has important pleiotropic effects on multiple body functions including immune system. Other types of vitamin D3 hydroxyderivatives are produced in vivo and are detectable in human body, which are biologically active with mechanism of action both differential and overlapping with classical 1,25(OH)2D3. Vitamin D3 hydroxyderivatives have been proved to be non-toxic in preclinical testing, endogenous products and detectable in natural products such as honey. Using high doses of vitamin D3 and its hydroxyderivatives for SARS-CoV-2 prevention and therapy is proposed but the exact mechanism of its action remain unknown. Cell entry of SARS-CoV-2 involves binding of receptor binding domain (RBD) of spike protein in SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) receptor, and cellular serine protease TMPRSS2 primes viral spike proteins in SARS-CoV-2. The hidden RBD of SARS-CoV-2 is critical to both vaccination and antibody neutralization due to its limited accessibility. A TMPRSS2 inhibitor approved for clinical use blocked viral entry. Molecules with potential to inhibit the interaction of SARS-CoV-2 RBD and ACE2 and as TMPRSS2 inhibitor could be an effective therapy to constrain cellular entry of SARS-CoV-2. Objective of this study is to determine the potential of vitamin D3 and its hydroxyderivatives as TMPRSS2 inhibitor and to inhibit ACE2 and SARS-CoV-2 RBD interaction using combined molecular docking, molecular dynamics simulation and binding free energy analyses. The results could propose vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19. We will implement the objective with two Specific Aims. Aim 1 is structure-based identification of vitamin D3 and its hydroxyderivatives to target human host proteins of ACE2 and TMPRSS2 and RBD of spike protein in SARS-CoV-2 using unbiased virtual screening. Aim 2 is combined molecular dynamics (MD) simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) binding free energy analyses to re-rank the top 10 ligands from initial virtual screening and to unveil the molecular and structural basis for the top ligand interactions with the human host proteins and RBD of spike protein in SARS-CoV-2.\n\nDiscovering vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19 and understanding its molecular and structural mechanisms, using the integrated molecular docking, MD simulation and binding free energy analyses in a quick and efficient manner, could inspire in vitro, in vivo and clinical trials in a rapid manner, further accelerating the translation to COVID-19 treatment to have immediate high impact.