In-silico evaluation of natural alkaloids against the main protease and spike glycoprotein as potential therapeutic agents for SARS-CoV-2

Abstract

Severe Acute Respiratory Syndrome Corona Virus (SARS-CoV-2) is the causative agent of COVID-19 pandemic, which has resulted in global fatalities since late December 2019. Alkaloids play a significant role in drug design for various antiviral diseases, which makes them viable candidates for treating COVID-19. To identify potential antiviral agents, 102 known alkaloids were subjected to docking studies against the two key targets of SARS-CoV-2, namely the spike glycoprotein and main protease. The spike glycoprotein is vital for mediating viral entry into host cells, and main protease plays a crucial role in viral replication; therefore, they serve as compelling targets for therapeutic intervention in combating the disease. From the selection of alkaloids, the top 6 dual inhibitory compounds, namely liensinine, neferine, isoliensinine, fangchinoline, emetine, and acrimarine F, emerged as lead compounds with favorable docked scores. Interestingly, most of them shared the bisbenzylisoquinoline alkaloid framework and belong to Nelumbo nucifera, commonly known as the lotus plant. Docking analysis was conducted by considering the key active site residues of the selected proteins. The stability of the top three ligands with the receptor proteins was further validated through dynamic simulation analysis. The leads underwent ADMET profiling, bioactivity score analysis, and evaluation of drug-likeness and physicochemical properties. Neferine demonstrated a particularly strong affinity for binding, with a docking score of -7.5025 kcal/mol for main protease and -10.0245 kcal/mol for spike glycoprotein, and therefore a strong interaction with both target proteins. Of the lead alkaloids, emetine and fangchinoline demonstrated the lowest toxicity and high LD50 values. These top alkaloids, may support the body’s defense and reduce the symptoms by their numerous biological potentials, even though some properties naturally point to their direct antiviral nature. These findings demonstrate the promising anti-COVID-19 properties of the six selected alkaloids, making them potential candidates for drug design. This study will be beneficial in effective drug discovery and design against COVID-19 with negligible side effects.

Identifying plant-derived antiviral alkaloids as dual inhibitors of SARS-CoV-2 main protease and spike glycoprotein through computational screening

“…Furthermore, to validate the binding mechanism of selected alkaloids and gain a more comprehensive understanding of interaction patterns, the reference drugs as well as apoproteins were analyzed using MD. As performed previously ( Shah et al, 2024 ), the evaluation of complex stability was based on comprehensive analyses, including RMSD and RMSF assessments. RoG and SASA analyses were also performed to evaluate the conformational changes throughout the simulation run.…”

“…Regarding the possible treatments for this disease, research has mainly focused on the invention of potential vaccines or designing potential drugs ( Liu et al, 2020 ; Jaan et al, 2021 ; Shah et al, 2024 ). So far, not even a single drug has been discovered or formulated specifically for the treatment of COVID-19 ( Vegad et al, 2023 ).…”

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson’s Disease through a Computational Approach

“…To ensure the accuracy and reliability of the screening through docking, we used a systematic validation process that included redocking and superimposition methods. , The reference alkaloid, papaverine, was docked into the specified active site of the PDE10A (PDB ID: 6MSA) using the MOE software. The resulting lowest energy pose of the papaverine–PDE10A complex was analyzed, and the characteristics of the ligand–protein binding site were recorded.…”

“…The permissible limit of flexibility is less than 10 rotatable bonds, in accordance with Lipinski's rule of five (RO5) for CNS-active drugs. Quinolines 2,3,5,6,8,9,14,16,25,27,29,34,39,40,and 42 did not meet this criterion. Other than these compounds, all quinolines and quinazolines reside within the admissible limit of molecular flexibility.…”