Repurposing of Drugs for SARS-CoV-2 Using Inverse Docking Fingerprints

Abstract

Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 is a virus that belongs to the Coronaviridae family. This group of viruses commonly causes colds but possesses a tremendous pathogenic potential. In humans, an outbreak of SARS caused by the SARS-CoV virus was first reported in 2003, followed by 2012 when the Middle East respiratory syndrome coronavirus (MERS-CoV) led to an outbreak of Middle East respiratory syndrome (MERS). Moreover, COVID-19 represents a serious socioeconomic and global health problem that has already claimed more than four million lives. To date, there are only a handful of therapeutic options to combat this disease, and only a single direct-acting antiviral, the conditionally approved remdesivir. Since there is an urgent need for active drugs against SARS-CoV-2, the strategy of drug repurposing represents one of the fastest ways to achieve this goal. An in silico drug repurposing study using two methods was conducted. A structure-based virtual screening of the FDA-approved drug database on SARS-CoV-2 main protease was performed, and the 11 highest-scoring compounds with known 3CLpro activity were identified while the methodology was used to report further 11 potential and completely novel 3CLpro inhibitors. Then, inverse molecular docking was performed on the entire viral protein database as well as on the Coronaviridae family protein subset to examine the hit compounds in detail. Instead of target fishing, inverse docking fingerprints were generated for each hit compound as well as for the five most frequently reported and direct-acting repurposed drugs that served as controls. In this way, the target-hitting space was examined and compared and we can support the further biological evaluation of all 11 newly reported hits on SARS-CoV-2 3CLpro as well as recommend further in-depth studies on antihelminthic class member compounds. The authors acknowledge the general usefulness of this approach for a full-fledged inverse docking fingerprint screening in the future.

Hypericum perforatum and Its Ingredients Hypericin and Pseudohypericin Demonstrate an Antiviral Activity against SARS-CoV-2

“…Several approaches were introduced to reveal potential antivirals against SARS-CoV-2. Among them, the first installed one was the usage of existing clinically approved drugs (i.e., re-purposing of drug usage) [ 15 ]. Nevertheless, undesired side effects may occur in terms of different doses, toxic effects, and pharmacological characteristics.…”

Mechanistic Insights into Biological Activities of Polyphenolic Compounds from Rosemary Obtained by Inverse Molecular Docking

“…The inverse molecular docking protocol based on the CANDOCK algorithm resulted in score variations for the detection of true target proteins (TG determined from PC has a value of 0.171), which in combination with ROC AUC above 0.6 indicates that the protocol provides good results in agreement with the experiments [ 61 ]. Moreover, our inverse molecular docking protocol has been already extensively validated by Fine and Konc et al [ 55 ], Furlan et al [ 50 , 130 ], Kores et al [ 49 , 131 ], and Jukič et al [ 132 ] using different molecules of interest.…”

Autochthonous Peruvian Natural Plants as Potential SARS-CoV-2 Mpro Main Protease Inhibitors

“…Enormous prevention efforts, including social distancing, regular use of masks and hand washing, have not prevented the spread of the virus [4]. Motivated by the rapid increase in cases and severe illness, much effort has been placed on the discovery of antivirals, by resorting to natural compounds or through drug repositioning strategies [5][6][7][8][9][10], along with vaccine development [11]. Although several commercialized drugs, such as Remdesivir [12] or Hydroxychloroquine [13], were initially repositioned as antivirals to treat severe COVID-19, subsequent large randomized clinical trials showed them to be ineffective or to exhibit unacceptable levels of side effects [14][15][16].…”

“…These features make M pro an attractive and obvious target to treat COVID-19. Designed druglike compounds such as noncovalent inhibitors [26], peptidomimetic inhibitors [23], drug repositioning and screening of natural compounds [5][6][7][8][9][10]21] are some examples of the strategies used to discover small molecules targeting SARS-CoV-2 M pro . In this regard, Virtual Screening represents an effective and reliable computational approach useful for the rapid identification of bioactive compounds directed against a target of interest [27,28], and thus many in silico studies have applied Virtual Screening protocols as the initial step towards the identification of potential M pro inhibitors [29][30][31][32][33], some of which have been experimentally confirmed [34][35][36][37].…”