The molecular dynamics of possible inhibitors for SARS-CoV-2

Abstract

The novel coronavirus SARS-CoV-2, responsible for the present COVID-19 global pandemic, is known to bind to the angiotensin converting enzyme-2 (ACE2) receptor in human cells. A possible treatment of COVID-19 could involve blocking ACE2 and/or disabling the spike protein on the virus. Here, molecular dynamics simulations were performed to test the binding affinities of nine candidate compounds. Of these, three drugs showed significant therapeutic potential that warrant further investigation: SN35563, a ketamine ester analogue, was found to bind strongly to the ACE2 receptor but weakly within the spike receptor-binding domain (RBD); in contrast, arbidol and hydroxychloroquine bound preferentially with the spike RBD rather than ACE2. A fourth drug, remdesivir, bound approximately equally to both the ACE2 and viral spike RBD, thus potentially increasing risk of viral infection by bringing the spike protein into closer proximity to the ACE2 receptor. We suggest more experimental investigations to test that SN35563—in combination with arbidol or hydroxychloroquine—might act synergistically to block viral cell entry by providing therapeutic blockade of the host ACE2 simultaneous with reduction of viral spike receptor-binding; and that this combination therapy would allow the use of smaller doses of each drug.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular dynamics
• computational simulation
• SARS-CoV-2

Acknowledgements

The simulations were performed using super-computing facilities available at the University of Waikato and also through the New Zealand eScience Infrastructure (NeSI).

Disclosure statement

No potential conflict of interest was reported by the author(s).