Researchers Screen 128 Compounds to Target SARS-CoV-2 Proteins in Computational Drug Repurposing Study
Computational researchers have screened 128 compounds against three critical SARS-CoV-2 proteins to build a pre-screened pool of candidates that could be rapidly evaluated if a similar viral outbreak were to recur, bioengineer.org reported. The in silico study, led by Triveni Singirisetty and published in the journal Green Technology, Resilience, and Sustainability, evaluated 89 FDA-approved antiviral drugs and 39 plant-derived molecules using molecular docking software.
The team targeted three specific viral components: the nsp15 endoribonuclease, the main protease, and the nsp16-nsp10 complex. Because two-thirds of the coronavirus genome encodes non-structural proteins that drive replication, simultaneously targeting these proteins offers a way to interfere with RNA processing, protein maturation, and RNA capping at different stages of the viral cycle.
The computational workflow used crystal structures from the Protein Data Bank—specifically 6VWW for nsp15, 6Y84 for the main protease, and 6W4H for the nsp16-nsp10 complex. Docking was performed with the licensed Schrödinger 2021_2 Glide Maestro tool, and results were ranked by glide scores and binding energy values in kilocalories per mole. Ramachandran plots validated the selected proteins before docking began.
Antiviral Drug and Plant Compound Rankings Across Viral Targets
Regarding the nsp15 target, remdesivir recorded the highest glide score among antiviral medications at -7.228, followed by ribavirin at -6.988, letermovir at -6.96, favipiravir at -6.823, and idoxuridine at -6.788. When considering binding energy instead, zidovudine stood out at -72.11 kcal/mol, alongside cobicistat, ritonavir, saquinavir, telaprevir, and daclatasvir in the -60 kcal/mol range.
Plant-derived molecules showed strong performance at the same nsp15 site. Epigallocatechin achieved a glide score of -7.596, amentoflavone scored -7.417, and quercetin reached -7.408, all outscoring remdesivir’s glide score at that target. Ent-epiafzelechin followed closely at -6.944.
When looking at the main protease, adefovir performed best among the antiviral treatments with a glide score of -7.527, with subsequent scores belonging to entecavir at -7.141, penciclovir at -7.07, ganciclovir at -6.852, and tenofovir at -6.624. Among natural compounds targeting the nsp16-nsp10 complex, ent-epiafzelechin scored -7.142, while other natural molecules also showed notable results.
At the nsp16-nsp10 complex, researchers screened the SAM binding site using co-crystallized S-adenosylmethionine as a reference standard, where SAM recorded a docking score of -10.06 and a binding energy of -76.49 kcal/mol. Vidarabine emerged as the closest antiviral lead at -9.399, while zidovudine displayed the lowest binding energy of the screen at -80.07 kcal/mol.
Simultaneously, a separate study reported by ScienceDirect evaluated natural compounds from medicinal plants against the spike glycoprotein and main protease Mpro using AutoDock. That study found binding energies of -19.22 kcal/mol for glycyrrhizin, -17.84 kcal/mol for gitoxin, and -9.36 kcal/mol for spirostan.
Validation Limits and Next Steps for Experimental Testing
The study by Singirisetty and colleagues is entirely computational, meaning results reflect predicted binding interactions rather than measured antiviral activity in cells, animals, or patients. The authors note that the identified compounds require thorough in vitro and in vivo validation studies before drawing therapeutic conclusions. Molecular dynamics simulations and free energy calculations were not performed, which the team recommends for future refinements.
As a preparedness exercise, the study narrows hundreds of possibilities into a manageable shortlist for laboratories to prioritize in experimental testing. Maintaining pre-validated leads among drugs with established safety profiles could accelerate responses to future coronavirus outbreaks once computational predictions face the rigors of laboratory testing.
Frequently Asked Questions About the in Silico Screening Study
What specific software was used to perform the molecular docking simulations?
The researchers performed docking using the licensed Schrödinger 2021_2 Glide Maestro tool, ranking results by glide scores and binding energy values expressed in kilocalories per mole.
Which natural compound achieved the strongest glide score against the nsp15 target?
Epigallocatechin achieved the highest glide score of -7.596 against the nsp15 endoribonuclease target, outperforming the top antiviral drug remdesivir.
What protein complex was evaluated using S-adenosylmethionine as a reference standard?
The nsp16-nsp10 complex was screened at the SAM binding site, where the co-crystallized reference standard SAM recorded a binding energy of -76.49 kcal/mol.
Did the study measure actual antiviral activity in human cells or animals?
No, the study is entirely in silico and represents predicted binding interactions rather than measured biological activity in cells, animals, or patients.