Abstract
The rapid spread of COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a worldwide health emergency. Unfortunately, to date, a very small number of remedies have been to be found effective against SARS-CoV-2 infection. Therefore, further research is required to achieve a lasting solution against this deadly disease. Repurposing available drugs and evaluating natural product inhibitors against target proteins of SARS-CoV-2 could be an effective approach to accelerate drug discovery and development. With this strategy in mind, we derived Marine Natural Products (MNP)-based drug-like small molecules and evaluated them against three major target proteins of the SARS-CoV-2 virus replication cycle. A drug-like database from MNP library was generated using Lipinski’s rule of five and ADMET descriptors. A total of 2,033 compounds were obtained and were subsequently subjected to molecular docking with 3CLpro, PLpro, and RdRp. The docking analyses revealed that a total of 14 compounds displayed better docking scores than the reference compounds and have significant molecular interactions with the active site residues of SARS-CoV-2 virus targeted proteins. Furthermore, the stability of docking-derived complexes was analyzed using molecular dynamics simulations and binding free energy calculations. The analyses revealed two hit compounds against each targeted protein displaying stable behavior, binding affinity, and molecular interactions. Our investigation identified two hit compounds against each targeted proteins displaying stable behavior, higher binding affinity and key residual molecular interactions, with good in silico pharmacokinetic properties, therefore can be considered for further in vitro studies.
Highlights
The world is experiencing a global public health emergency due to the outbreak of coronavirus disease 2019 (COVID-19), which is caused by a novel virus known as severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2; Gorbalenya et al, 2020; Sohrabi et al, 2020)
The structural proteins of SARS-CoV-2 are the enveloped protein (E protein) which helps in morphogenesis during the assemblage of the viral genome, the membrane protein (M protein) which maintains the shape of the virus envelope, and the nucleocapsid (N protein) which is responsible for RNA binding and dimerization (Fehr and Perlman, 2015; Schoeman and Fielding, 2019; Astuti and Ysrafil, 2020)
It has been reported that drugs like Lopinavir, Ritonavir, Remdesivir, Umifenovir, and Favipiravir are under clinical trials against SARS- CoV-2 target proteins (Drozdzal et al, 2020; Pawar, 2020), these drugs have been reported to show severe side effects in COVID-19 patients (Fan et al, 2020a; Khan et al, 2020b; Türsen et al, 2020)
Summary
The world is experiencing a global public health emergency due to the outbreak of coronavirus disease 2019 (COVID-19), which is caused by a novel virus known as severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2; Gorbalenya et al, 2020; Sohrabi et al, 2020). After the entry of the SARSCoV-2 into the cell, the replication of the coronavirus starts with the translation of two overlapping open reading frames (ORF1a and ORF1b) to produce pp1a and pp1ab, generated by a ribosomal frameshift mechanism (Astuti and Ysrafil, 2020; Gul et al, 2020; Kim et al, 2020) These polyproteins are processed proteolytically by two essential viral cysteine proteasespapain-like protease or PLpro (non-structural protein 3 or nsp 3) and 3C-like protease (3CLpro, known as the main protease, Mpro, or nsp5) (Chen et al, 2020b). We designed a virtual screening study for the search of novel drug-like molecules against NSPs 3CLpro, PLpro, and RdRp—deemed as key proteins required for the virus replication cycle of SARS-CoV-2— considered as attractive drug targets (Chellapandi and Saranya, 2020; Li and De Clercq, 2020; Muhammed, 2020)
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