Research related to SARS-CoV-2 drugs is still ongoing. In this initial research, we perform a computational approach on SARS-CoV-2 inhibitors. RNA-dependent RNA polymerase (RdRp) is one of the functional proteins in SARS-CoV-2 that can be a target for drug development, which has an essential function in the viral replication process synthesizing the RNA genome of the virus. This study used the RdRp-Remdesivir complex structure from RCSB with ID PDB 7BV2, with a resolution of 2.5 Å. Currently, Remdesivir is under the clinical trial phase as a Covid-19 drug. In this study, we tested a thousand natural Indonesian compounds used as SARS-CoV-2 RdRp inhibitors obtained from the Indonesian natural compounds database (HerbalDB). The first stage of this computational analysis was pharmacophore modeling structure-based drug design. The natural compounds were analyzed based on their steric and electronic similarities to Remdesivir. A molecular docking simulation was then performed to obtain binding energy and bond stability to produce natural compounds that can inhibit RdRp SARS-CoV-2. The final stage was the molecular dynamics simulation that explored the conformational space of natural compounds and proteins. The ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) test was carried out on the five best compounds to obtain these natural compounds' computational pharmacology and pharmacokinetics. The simulation identified Sotetsuflavone (CID: 5494868) from Cycas revoluta, Grossamide (CID: 5322012) from Cannabis sativa, and 6-Hydroxyluteolin-6,7-disulfate (CID: 13845917) from Lippia nodiflora are the best compounds that can inhibit RdRp SARS-CoV-2. These potential compounds can then be tested in-vitro and in-vivo in the future.

Lipid nanoparticles (LNPs) have emerged as a promising delivery system, particularly for genetic therapies and vaccines. LNP formation requires a specific mixture of nucleic acid in a buffered solution and lipid components in ethanol. Ethanol acts as a lipid solvent, aiding the formation of the nanoparticle’s core, but its presence can also affect LNP stability. In this study, we used molecular dynamics (MD) simulations to investigate the physicochemical effect of ethanol on LNPs and gain a dynamic understanding of its impact on the overall structure and stability of LNPs. Our results demonstrate that ethanol destabilizes LNP structure over time, indicated by increased root mean square deviation (RMSD) values. Changes in the solvent-accessible surface area (SASA), electron density, and radial distribution function (RDF) also suggest that ethanol affects LNP stability. Furthermore, our H-bond profile analysis shows that ethanol penetrates the LNP earlier than water. These findings emphasize the importance of immediate ethanol removal in lipid-based systems during LNP production to ensure stability.

The computational method provides an alternative approach for conducting screening of natural substances antiviral properties against the SARS-CoV-2 virus. This research focuses on the Main Protease, a target protein that plays a central role in viral replication by producing an enzyme that cleaves the host protein nuclear factor (NF)-κB in SARS-CoV-2. The study used a thousand natural compound structures from the Indonesian Natural Compound Database (Herbaldb), filtered based on the similarity of their pharmacophore features with Mainprotease inhibitors. In compounds with good pharmacophore properties, docking will be carried out to determine the binding affinity with the target protein and obtain the complex structure. The ADMETSAR test was used to determine the pharmacology and pharmacokinetics of the five best natural compounds. Finally, molecular dynamics simulation of the complex structure was performed to assess the stability of the best compound interactions with the SARS-CoV-2 Mainprotease. The compounds identified as Mainprotease inhibitors in this study were cosmosiin, glucobrassicin, and isobavachin.