Putative Inhibitors of SARS-CoV-2 Main Protease from A Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study

TLDR

COVID‑19, caused by SARS‑CoV‑2, poses a global public‑health emergency, and past coronavirus outbreaks (SARS, MERS) highlight the need for new drugs; the viral main protease (Mpro) is a validated target, with HIV protease inhibitors like lopinavir proposed for treatment though their efficacy remains unconfirmed. The study aims to identify potent Mpro inhibitors from a marine natural product library using computational screening. The authors used a pharmacophore model and docking to screen a marine natural product library, followed by molecular dynamics and re‑docking to validate the hits. Seventeen marine natural products were identified as potential SARS‑CoV‑2 Mpro inhibitors, and consensus docking plus molecular dynamics support a high likelihood of bioactivity.

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.