Vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19: a computational study

Abstract

The epidemiologic correlation between the poor prognosis of SARS-CoV-2 infection and vitamin D deficiency has been observed worldwide, however, their molecular mechanisms are not fully understood. In this study, we used combined molecular docking, molecular dynamics simulations and binding free energy analyses to investigate the potentials of vitamin D3 and its hydroxyderivatives as TMPRSS2 inhibitor and to inhibit the SARS-CoV-2 receptor binding domain (RBD) binding to angiotensin-converting enzyme 2 (ACE2), as well as to unveil molecular and structural basis of 1,25(OH)₂D3 capability to inhibit ACE2 and SARS-CoV-2 RBD interactions. The results show that vitamin D3 and its hydroxyderivatives are favorable to bind active site of TMPRSS2 and the binding site(s) between ACE2 and SARS-CoV2-RBD, which indicate that vitamin D3 and its biologically active hydroxyderivatives can serve as TMPRSS2 inhibitor and can inhibit ACE2 binding of SARS-CoV-2 RBD to prevent SARS-CoV-2 entry. Interaction of 1,25(OH)₂D3 with SARS-CoV-2 RBD and ACE2 resulted in the conformation and dynamical motion changes of the binding surfaces between SARS-CoV-2 RBD and ACE2 to interrupt the binding of SARS-CoV-2 RBD with ACE2. The interaction of 1,25(OH)₂D3 with TMPRSS2 also caused the conformational and dynamical motion changes of TMPRSS2, which could affect TMPRSS2 to prime SARS-CoV-2 spike proteins. Our results propose that vitamin D3 and its biologically active hydroxyderivatives are promising drugs or adjuvants in the treatment of COVID-19.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• vitamin D3 and its hydroxyderivatives
• ACE2
• SARS-CoV-2 RBD
• TMPRSS2
• molecular docking
• molecular dynamics simulation
• binding free energy analysis

Disclosure statement

The authors declare that there are no conflicts of interest.

Author’s contribution

Yuwei Song: investigation, data curation, formal analysis, writing, visualization; Shariq Qayyum: conceptualization, writing; Rory A. Greer: data curation, writing, visualization; Radomir M. Slominski: conceptualization, writing; Chander Raman: conceptualization, writing; Andrzej T. Slominski: conceptualization, writing, supervision, project administration; Yuhua Song: conceptualization, methodology, writing, supervision, project administration.

Data availability statement

Force field of 1,25(OH)₂D3, constructed TMPRSS2 structure, the docking complex structures and MD simulation trajectories are available upon request.

Additional information

Funding

The study was supported by NIH grants 1R01AR073004-01A1 and R01AR071189-01A1 to ATS, R21 AI152047-01A1 to CR and ATS, pilot grant from Hugh Kaul Precision Medicine Institute at University of Alabama at Birmingham (UAB) (YHS). This work was enabled by COVID-19 High-Performance Computing (HPC) Consortium award (TG-BIO200084 for YHS, ATS and YWS) with computational resources from the Extreme Science and Engineering Discovery Environment (XSEDE) and was also enabled by the high-performance computing recourses at UAB IT Research Computing.