[Paper Review] Searching inhibitors for three important proteins of COVID-19 through molecular docking studies

Seshu Vardhan, Sahoo Sk|arXiv (Cornell University)|Apr 17, 2020

Diverse Scientific Research Studies15 references17 citations

TL;DR

This study used molecular docking to evaluate 18 ligands—primarily phytochemicals—against three key SARS-CoV-2 targets: RNA-dependent RNA polymerase (RdRp), ACE2, and spike glycoprotein (SGp). It found that terpenoid compounds limonin and scopadulcic acid B exhibited superior binding affinities compared to hydroxychloroquine and paracetamol, suggesting their potential as anti-COVID-19 candidates for further experimental validation.

ABSTRACT

The lack of recommended drugs or vaccines to deal with the COVID-19 is the main concern of this pandemic. The approved drugs for similar health problems, drugs under clinical trials, and molecules from medicinal plants extracts are investigated randomly to deal with the COVID-19 infection. Molecular docking, one of the best approach to search therapeutically potent drugs/molecules in real time with possible hope to apply on COVID-19. In this communication, molecular docking studies of 18 ligands were carried out with the three therapeutic target proteins of SARS-CoV-2, i.e., RNA-dependent RNA polymerase (RdRp), angiotensin-converting enzyme 2 (ACE2) and spike glycoprotein (SGp). The obtained results revealed that the phytochemicals showed better dock score in compared to the drugs paracetmol and hydroxychloroquine. Combining the dock score and medicinal properties, we believe the terpenoids based phytochemicals limonin and scopadulcic acid B can be further explored for potential use against COVID-19.

Motivation & Objective

• To identify potential small-molecule inhibitors targeting key SARS-CoV-2 proteins involved in viral replication and host entry.
• To evaluate both approved drugs and natural phytochemicals for their inhibitory potential against SARS-CoV-2 targets.
• To prioritize lead compounds based on docking scores and medicinal properties for further preclinical investigation.
• To provide in silico evidence supporting repurposing of natural compounds as anti-COVID-19 therapeutics.

Proposed method

• Molecular docking was performed using AutoDock Vina to predict binding affinities between ligands and three SARS-CoV-2 target proteins: RdRp, ACE2, and SGp.
• A total of 18 ligands were screened, including FDA-approved drugs (paracetamol, hydroxychloroquine) and phytochemicals from medicinal plants.
• Protein structures were retrieved from the Protein Data Bank (PDB), with proper preparation including removal of water molecules and addition of polar hydrogens.
• Docking scores (in kcal/mol) were used as a primary metric to rank ligand affinity, with lower (more negative) values indicating stronger binding.
• Medicinal properties and structural features of top-scoring ligands were analyzed to assess drug-likeness and potential therapeutic relevance.
• The study focused on comparing docking results across ligands to identify candidates with superior binding potential over existing drugs.

Experimental results

Research questions

• RQ1 Which small molecules exhibit the strongest predicted binding affinity toward SARS-CoV-2’s RNA-dependent RNA polymerase (RdRp)?
• RQ2 How do the docking scores of natural phytochemicals compare to those of repurposed drugs like hydroxychloroquine and paracetamol against key viral targets?
• RQ3 Which phytochemicals show both high binding affinity and favorable medicinal properties for potential anti-COVID-19 drug development?
• RQ4 Can molecular docking identify lead compounds from natural sources that outperform current clinical candidates in silico?

Key findings

• Limonin and scopadulcic acid B exhibited the most favorable docking scores among all 18 ligands tested, indicating strong potential for binding to SARS-CoV-2 targets.
• The docking scores of these two terpenoid phytochemicals were significantly lower (more negative) than those of paracetamol and hydroxychloroquine, suggesting superior binding affinity.
• Phytochemicals generally outperformed conventional drugs in terms of predicted binding energy, highlighting their potential as lead compounds.
• The combination of high docking scores and favorable medicinal properties supports limonin and scopadulcic acid B as promising candidates for further experimental validation.
• The study identified a set of natural compounds with strong in silico inhibition potential, particularly against RdRp and spike glycoprotein, which are critical for viral replication and cell entry.
• The results suggest that natural products, especially terpenoids, may offer a viable alternative or complement to existing repurposed drugs in the fight against SARS-CoV-2.