Abstract
Structure-based drug design targeting the SARS-CoV-2 virus has been greatly facilitated by available virus-related protein structures. However, there is an urgent need for effective, safe small-molecule drugs to control the spread of the virus and variants. While many efforts are devoted to searching for compounds that selectively target individual proteins, we investigated the potential interactions between eight proteins related to SARS-CoV-2 and more than 600 compounds from a traditional Chinese medicine which has proven effective at treating the viral infection. Our original ensemble docking and cooperative docking approaches, followed by a total of over 16-micorsecond molecular simulations, have identified at least 9 compounds that may generally bind to key SARS-CoV-2 proteins. Further, we found evidence that some of these compounds can simultaneously bind to the same target, potentially leading to cooperative inhibition to SARS-CoV-2 proteins like the Spike protein and the RNA-dependent RNA polymerase. These results not only present a useful computational methodology to systematically assess the anti-viral potential of small molecules, but also point out a new avenue to seek cooperative compounds toward cocktail therapeutics to target more SARS-CoV-2-related proteins.
Highlights
Despite the availability of vaccines, there is still an urgent need for small molecules that are effective against SARS-CoV-2, the virus which causes the COVID-19 disease in the current pandemic
We have developed our computational methodology which is comprised of ensemble docking, cooperative docking, and extensive molecular dynamics (MD) simulations for the systems chemistry investigation
We have identified at least nine compounds that broadly interact with the six SARS-CoV-2 proteins as well as the angiotensin converting enzyme 2 (ACE2) enzymes, with affinities predicted mostly between − 5 and − 15 kcal/mol (Fig. 1 and Table 1)
Summary
Despite the availability of vaccines, there is still an urgent need for small molecules that are effective against SARS-CoV-2, the virus which causes the COVID-19 disease in the current pandemic. As QPD is administrated in clinical practice as a mixture of many bioactive compounds from the herbs, a systematic study is required to understand the individual and joint interactions between these compounds and the SARS-CoV-2 proteins To fulfil this need, we have developed our computational methodology which is comprised of ensemble docking, cooperative docking, and extensive molecular dynamics (MD) simulations for the systems chemistry investigation. We have identified several compounds which potentially inhibit multiple SARS-CoV-2 proteins; compounds from the same or different herbs may have synergy to enhance binding to the viral proteins These findings shed light on new directions of COVID-19 treatments
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