Abstract
The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (Mpro) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpro inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpro inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.
Highlights
The new coronavirus, designated as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), was first identified in Wuhan, China, in December 2019 [1]
Our work aims to perform a virtual screening against the SARS-CoV-2 main protease (Mpro) binding site using the library of Marine Natural Products (MNP)
Docking studies highlighted that interactions between dieckol and the amino acid residues in the active site of Mpr are mainly constituted by a H-bonds network with a calculated binding energy of −11.76 kcal/mol [26], that is comparable to the energy found by us with the SARS-CoV-2 Mpr
Summary
The new coronavirus, designated as severe acute respiratory syndrome coronavirus 2. SARS-CoV-2 Mpro and SARS-CoV-1 Mpro structures are quite similar, the main difference being the surface of the proteins, where 12 different amino acids are located Both enzymes consist of three domains; the domains I (residues 1–101) and II (residues 102–184) consist of an antiparallel β-barrel, and, for enzymatic activity, the α-helical domain III is required (residues 201–301) [9,10,11]. Mpro structures, suggesting that the SARS Mpro binding cavity is highly flexible and shows significant changes in both volume and shape after ligand binding [10,11] These features can be exploited in the design of lead compounds with a potentially broad spectrum of activity. 17 molecules that showed the most promising results in terms of inhibitory activity
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