Virtual Screening on Marine Natural Products for Discovering TMPRSS2 Inhibitors

Abstract

Although SARS-CoV-2 entry to cells strictly depends on angiotensin-converting enzyme 2 (ACE2), the virus also needs transmembrane serine protease 2 (TMPRSS2) for its spike protein priming. It has been shown that the entrance of SARS-CoV-2 through ACE2 can be blocked by cellular TMPRSS2 blockers. The main aim of this study was to find potential inhibitor(s) of TMPRSS2 through virtual screening against a homology model of TMPRSS2 using the library of marine natural products (MNPs). The homology modeling technique for generating a three-dimensional structure of TMPRSS2 was applied. Molecular docking, MM-GBSA and absorption, distribution, metabolism, excretion (ADME) evaluations were performed to investigate the inhibitory activity of marine natural products (MNPs) against TMPRSS2 and their pharmacokinetic properties. Camostat and nafamostat mesylate were used as the standard inhibitory molecules. Seven MNPs were able to inhibit TMPRSS2 better than the standard compounds. MNP 10 with CAS number 107503-09-3, called Watasenia β-D- Preluciferyl glucopyrasoiuronic acid, was found to be the best inhibitor of TMPRSS2 with acceptable pharmacokinetic properties. Herein, for the first time, a new marine natural product was introduced with potent inhibitory effects against TMPRSS2. MNP 10 exhibited favorable drug-like pharmacokinetic properties and it promises a novel TMPRSS2 blocker to combat SARS-CoV-2.

Molecular docking-based virtual screening: Challenges in hits identification for Anti-SARS-Cov-2 activity

“…According to our findings, 11.6% of articles used homology structure in their docking studies for several targets such as TMPRSS2 (Barge et al 2021;Idris et al 2021;Mahmudpour et al 2021), S (Mathew et al 2021), ACE2 (Srivastava et al 2021), and helicase (White et al 2020). Indeed, the similarity between the protein sequence of SARS-Cov-2 and SARS-Cov as the template is high (Dong et al 2020).…”

Structures of the SARS-CoV-2 spike glycoprotein and applications for novel drug development

“…Traditionally, natural products are important sources for novel drug development due to their rich sources, chemical diversity, large chemical space diversity, and biological activities. Therefore, natural products could make good starting points for modern drug design for the treatment of COVID-19 ( Hu et al, 2021a ; Mahmudpour et al, 2021 ). Together with the combination of computer-aided drug design and biological verification, drug development based on natural products is believed to be an efficient strategy for modern drug discovery.…”

In-Silico Approaches for the Screening and Discovery of Broad-Spectrum Marine Natural Product Antiviral Agents Against Coronaviruses

“…A recent success was a study aiming to discover potential inhibitor(s) of Transmembrane protease, serine 2 (TMPRSS2) via virtual screening against a homology model of TMPRSS2 using the library of marine natural products (MNPs). 95 Molecular docking, binding affinity analysis using MM-GBSA and ADME evaluations were carried out to explore the inhibitory activity of MNPs against TMPRSS2 and determine their pharmacokinetic properties. Seven MNPs inhibited TMPRSS2 and one in particular, MNP-10 or Watasenia β-D- Preluciferyl glucopyrasoiuronic acid, was the optimal inhibitor of TMPRSS2 with acceptable pharmacokinetic properties.…”