Dengue fever is a significant public health concern throughout the world, causing an estimated 500,000 hospitalizations and 20,000 deaths each year, despite the lack of effective therapies. The DENV-2 RdRp has been identified as a potential target for the development of new and effective dengue therapies. This research’s primary objective was to discover an anti-DENV inhibitor using in silico ligand- and structure-based approaches. To begin, a ligand-based pharmacophore model was developed, and 130 distinct natural products (NPs) were screened. Docking of the pharmacophore-matched compounds were performed to the active site of DENV-2 RdRp protease . Eleven compounds were identified as potential DENV-2 RdRp inhibitors based on docking energy and binding interactions. ADMET and drug-likeness were done to predict their pharmacologic, pharmacokinetic, and drug-likeproperties . Compounds ranked highest in terms of pharmacokinetics and drug-like appearances were then subjected to additional toxicity testing to determine the leading compound. Additionally, MD simulation of the lead compound was performed to confirm the docked complex’s stability and the binding site determined by docking. As a result, the lead compound (compound-108) demonstrated an excellent match to the pharmacophore, a strong binding contact and affinity for the RdRp enzyme, favourable pharmacokinetics, and drug-like characteristics. In summary, the lead compound identified in this study could be a possible DENV-2 RdRp inhibitor that may be further studied on in vitro and in vivo models to develop as a drug candidate. Communicated by Ramaswamy H. Sarma

Due to the rising increase in infectious diseases brought on by bacteria and anti-bacterial drug resistance, antibacterial therapy has become difficult. The majority of first-line antibiotics are no longer effective against numerous germs, posing a new hazard to global human health in the 21st century. Through the drug-likeness screening, 184 usnic acid derivatives were selected from an in-house database of 340 usnic acid compounds. The pharmacokinetics (ADMET) prediction produced fifteen hit compounds, of which the lead molecule was subsequently obtained through a molecular docking investigation. The lead compounds, labelled compound-277 and compound-276, respectively, with the substantial binding affinity towards the enzymes were obtained through further docking simulation on the DNA gyrase and DNA topoisomerase proteins. Additionally, molecular dynamic (MD) simulation was performed for 300 ns on the lead compounds in order to confirm the stability of the docked complexes and the binding pose discovered during docking tests. Due to their intriguing pharmacological characteristics, these substances may be promising therapeutic candidate for anti-bacterial medication. Communicated by Ramaswamy H. Sarma

Usnic acid (UA) lately piqued the interest of researchers for its extraordinary biological characteristics, including anticancer activity. Here, the mechanism was clarified through network pharmacology,molecular docking and molecular dynamic simulation. Sixteen proteins were selected through network pharmacology study as they are probable to interact with UA. Out of these proteins, 13 were filtered from PPI network analysis based on their significance of interactions (p < 0.05). KEGG pathway analysis has also aided us in determining the three most significant protein targets for UA, which are BCL2, PI3KCA and PI3KCG. Therefore molecular docking and molecular dynamic (MD) simulations throughout 100 ns were performed for usnic acid onto the three proteins mentioned. However, UA's docking score in all proteins is lower than their co-crystalised ligand, especially for BCL2 (−36.5158 kcal/mol) and PI3KCA (−44.5995 kcal/mol) proteins. The only exception is PI3KCG which has comparable results with the co-crystallised ligand with (−41.9351 kcal/mol). Furthermore, MD simulation has also revealed that usnic acid does not stay fit in the protein throughout the simulation trajectory for PI3KCA protein evident from RMSF and RMSD plots. Nevertheless, it still poses good ability in inhibiting BCL2 and PI3KCG protein in MD simulation. In the end, usnic acid has exhibited good potential in the inhibition of PI3KCG proteins, rather than the other proteins mentioned. Thus further study on structural modification of usnic acid could enhance the ability of usnic acid in the inhibition of PI3KCG as anti-colorectal and anti-small cell lung cancer drug candidate. Communicated by Ramaswamy H. Sarma

Numerous malignancies, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia, are brought on by aberrant tyrosine kinase signaling. Since the current chemotherapeutic medicines are toxic, there is a great need and demand from cancer patients to find novel chemicals that are toxic-free or have low toxicity and that can kill tumor cells and stop their growth. This work describes the in-silico examination of substances from the drug bank as EGFR inhibitors. Firstly, drug-bank was screened using the pharmacophore technique to select the ligands and Erlotinib (DB00530) was used as matrix compound. The selected ligands were screened using ADMET and the hit compounds were subjected to docking. The lead compound from the docking was subjected to DFT and MD simulation study. Using the pharmacophore technique, 23 compounds were found through virtual drug bank screening. One hit molecule from the ADMET prediction was the subject of docking study. According to the findings, DB03365 molecule fits to the EGFR active site by several hydrogen bonding interactions with amino acids. Furthermore, DFT analysis revealed high reactivity for DB03365 compound in the binding pocket of the target protein, based on E_LUMO, E_HOMO and band energy gap. Furthermore, MD simulations for 100 ns revealed that the ligand interactions with the residues of EGFR protein were part of the essential residues for structural stability and functionality. However, DB03365 was a promising lead molecule that outperformed the reference compound in terms of performance and in-vitro and in-vivo experiments needs to validate the study.Communicated by Ramaswamy H. Sarma.

The goal of this work is to use a variety of in-silico techniques to identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, five main curcumin analogues were docked into the active site of DPP-IV enzyme. In comparison to the control molecule (Saxagliptin, -6.9 kcal/mol), all the compounds have the highest binding affinity (-7.6 to -7.7 kcal/mol) for the DPP-IV enzyme. These compounds underwent further testing for studies on drug-likeness, pharmacokinetics, and acute toxicity to see the efficacy and safety of compounds. To assess the stability of the docking complex and the binding posture identified during the docking experiment, our study got THC as the lead compound, which was then exposed to 200 ns of molecular dynamic simulation and PCA analysis. Additionally, DFT calculations were conducted to determine the thermodynamic, molecular orbital, and electrostatic potential characteristics of lead compound. Overall, the lead chemical has shown strong drug-like properties, is non-toxic, and has a sizable affinity for the DPP-IV enzyme.Communicated by Ramaswamy H. Sarma.

Diabetes affects millions globally and poses treatment challenges. Targeting the enzyme fructose-1,6-bisphosphatase (FBPase) in gluconeogenesis and exploring plant-based therapies offer potential solutions for improving diabetes management while supporting sustainability and medicinal advancements. Utilizing pineapple (Ananas comosus L. Merr.) waste as a source of drug precursors could be valuable for health and environmental care due to its medicinal benefits and abundant yearly biomass production. Therefore, this study conducted a virtual screening to identify potential natural compounds from pineapple that could inhibit FBPase activity. A total of 112 compounds were screened for drug-likeness and ADMET properties, and molecular docking simulations were performed on 20 selected compounds using blind docking. The lead compound, butane-2,3-diyl diacetate, was subjected to 100 ns MD simulations, revealing a binding energy of -5.4 kcal/mol comparable to metformin (-5.6 kcal/mol). The MD simulation also confirmed stable complexes with crucial hydrogen bonds. Glu20, Ala24, Thr27, Gly28, Glu29, Leu30, Val160, Met177, Asp178, and Cys179 were identified as key amino acids that stabilized the human liver FBPase-butane-2,3-diyl diacetate complex, while Tyr215 and Asp218 played a crucial role in the human liver FBPase-Metformin complex. Our study indicates that the lead compound has high intestinal solubility. Therefore, it would show rapid bloodstream distribution and effective action on the target protein, making butane-2,3-diyl diacetate a potential antidiabetic drug candidate. However, further investigations in vitro, preclinical, and clinical trials are required to thoroughly assess its efficacy and safety.Communicated by Ramaswamy H. Sarma.