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Repositioning therapeutics for COVID-19: virtual screening of the potent synthetic and natural compounds as SARS-CoV-2 3CLpro inhibitors

ABSTRACT: The widespread transmission of SARS-CoV-2 has sparked alarm worldwide. Attaining the best drugs to treat COVID-19 at the shortest possible time is one of the most critical issues in this urgent situation. Molecular docking investigation of the therapeutic potential of marketed drugs is a fast and cost-effective approach to provide a solution to this problem. The recent research efforts have led to the resolving of the 3CLpro structure as a key protease in the lifecycle of coronavirus, which could facilitate in silico evaluation of drug candidates. Herein, the similarity between the SARS-CoV-2-3CL main protease and the other SARS-CoV receptors was evaluated via multiple sequence alignment and phylogenetic tree. The reported structure of the 3CLpro was considered as a target to identify potential inhibitors for treating COVID-19 using molecular docking based virtual screening protocol. Accordingly, a database of 50 synthetic compounds with various pharmacological usage such as antiviral, anti-inflammatory, anti-human immunodeficiency viruses, antimalarial, antibacterial, anticancer, and antioxidant including approved drugs and those undergoing clinical trials, and 40 natural compounds particularly those employed in traditional Iranian medicine was constructed. The output of multiple sequence alignment analysis showed that SARS-CoV-2 main protease shares a similarity of 96% with SARS-CoV. Also, the docking results indicated that the licofelone acyl glucuronide as an anti-inflammatory drug and delta-bilirubin as an antioxidant and anti-inflammatory agent as well as kappa-carrageenan conformer, beta-D-galactopyranosyl and calycosin 7-O-glucoside as natural compounds with minimal side-effects, according to in vitro studies, are good candidates to block the enzymatic activity of SARS-CoV-2 3CLpro. Moreover, the compound 1 with the highest negative binding energy is a chemical compound that due to its favorable interactions with the 3CLpro can be identified as a representative potential drug candidate for COVID-19.

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Supplementary Information

The online version contains supplementary material available at 10.1007/s13738-021-02235-7.

SUBMITTER: Sattari A

PROVIDER: S-EPMC7994965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics. 3CLpro, the main protease responsible for the processing of viral polypeptide, plays a vital role in SARS-CoV-2 viral replication and translation and is an important target in other coronaviruses. Additionally, 3CLpro is the target of repurposed drugs, such as lopinavir and ritonavir. In this study, target proteins were retrieved from the protein data bank (PDB IDs: 6 M03, 6LU7, 2GZ7, 6 W63, 6SQS, 6YB7, and 6YVF) representing different open states of the main protease to accommodate macromolecular substrate. A hydroxyethylamine (HEA) library was constructed from harvested chemical structures from all the series being used in our laboratories for screening against malaria and Leishmania parasites. The database consisted of ∼1000 structure entries, of which 70% were new to ChemSpider at the time of screening. This in-house library was subjected to high throughput virtual screening (HTVS), followed by standard precision (SP) and then extra precision (XP) docking (Schrodinger LLC 2021). The ligand strain and complex energy of top hits were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Promising hit compounds (n = 40) specifically binding to 3CLpro with high energy and average MM/GBSA scores were then subjected to (100-ns) MD simulations. Using this sequential selection followed by an in-silico validation approach, we found a promising HEA-based compound (N,N'-((3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide)), which showed high in vitro antiviral activity against SARS-CoV-2. Further to reduce the size of the otherwise larger ligand, a pharmacophore-based predicted library of ∼42 derivatives was constructed, which were added to the previous compound library and rescreened virtually. Out of several hits from the predicted library, two compounds were synthesized, tested against SARS-CoV-2 culture, and found to have markedly improved antiviral activity.

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Repositioning therapeutics for COVID-19: virtual screening of the potent synthetic and natural compounds as SARS-CoV-2 3CLpro inhibitors

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Supplementary Information

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