Reporting multitargeted potency of Tiaprofenic acid against lung cancer: Molecular fingerprinting, MD simulation, and MTT-based cell viability assay studies.

Lung Cancer (LC) is among the most death-causing cancers, has caused the most destruction and is a gender-neutral cancer, and WHO has kept this cancer on its priority list to find the cure. We have used high-throughput virtual screening, standard precision docking, and extra precise docking for extensive screening of Drug Bank compounds, and the uniqueness of this study is that it considers multiple protein targets of prognosis and metastasis of LC. The docking and MM\GBSA calculation scores for the Tiaprofenic acid (DB01600) against all ten proteins range from -8.422 to -5.727 kcal/mol and - 47.43 to -25.72 kcal/mol, respectively. Also, molecular fingerprinting helped us to understand the interaction pattern of Tiaprofenic acid among all the proteins. Further, we extended our analysis to the molecular dynamic simulation in a neutralised SPC water medium for 100 ns. We analysed the root mean square deviation, fluctuations, and simulative interactions among the protein, ligand, water molecules, and protein-ligand complexes. Most complexes have shown a deviation of <2 Å as cumulative understanding. Also, the fluctuations were lesser, and only a few residues showed the fluctuation with a huge web of interaction between the protein and ligand, providing an edge that supports that the protein and ligand complexes were stable. In the MTT-based Cell Viability Assay, Tiaprofenic Acid exhibited concentration-dependent anti-cancer efficacy against A549 lung cancer cells, significantly reducing viability at 100 µg/mL. These findings highlight its potential as a therapeutic candidate, urging further exploration into the underlying molecular mechanisms for lung cancer treatment.

Integrative analysis discovers Imidurea as dual multitargeted inhibitor of CD69, CD40, SHP2, lysozyme, GATA3, cCBL, and S-cysteinase from SARS-CoV-2 and M. tuberculosis.

Two of the deadliest infectious diseases, COVID-19 and tuberculosis (TB), have combined to establish a worldwide pandemic, wreaking havoc on economies and claiming countless lives. The optimised, multitargeted medications may diminish resistance and counter them together. Based on computational expression studies, 183 genes were co-expressed in COVID-19 and TB blood samples. We used the multisampling screening algorithms on the top ten co-expressed genes (CD40, SHP2, Lysozyme, GATA3, cCBL, SIVmac239 Nef, CD69, S-adenosylhomocysteinase, Chemokine Receptor-7, and Membrane Protein). Imidurea is a multitargeted inhibitor for COVID-19 and TB, as confirmed by extensive screening and post-filtering utilising MM\GBSA algorithms. Imidurea has shown docking and MM\GBSA scores of -8.21 to -4.75 Kcal/mol and -64.16 to -29.38 Kcal/mol, respectively. The DFT, pharmacokinetics, and interaction patterns suggest that Imidurea may be a drug candidate, and all ten complexes were tested for stability and bond strength using 100 ns for all MD atoms. The modelling findings showed the complex's repurposing potential, with a cumulative deviation and fluctuation of <2 Å and significant intermolecular interaction, which validated the possibilities. Finally, an inhibition test was performed to confirm our in-silico findings on SARS-CoV-2 Delta variant infection, which was suppressed by adding imidurea to Vero E6 cells after infection.

Microbial Biofilm Inhibition Using Magnetic Cross-Linked Polyphenol Oxidase Aggregates.

Microbial biofilm accumulation poses a serious threat to the environment, presents significant challenges to different industries, and exhibits a large impact on public health. Since there has not been a conclusive answer found despite various efforts, the potential green and economical methods are being focused on, particularly the innovative approaches that employ biochemical agents. In the present study, we propose a bio-nanotechnological method using magnetic cross-linked polyphenol oxidase aggregates (PPO m-CLEA) for inhibition of microbial biofilm including multidrug resistant bacteria. Free PPO solution showed only 55-60% biofilm inhibition, whereas m-CLEA showed 70-75% inhibition, as confirmed through microscopic techniques. The carbohydrate and protein contents in biofilm extracellular polymeric substances (EPSs) were reduced significantly. The m-CLEA demonstrated reusability up to 5 cycles with consistent efficiency in biofilm inhibition. Computational work was also done where molecular docking of PPO with microbial proteins associated with biofilm formation was conducted, resulting in favorable binding scores and inter-residual interactions. Overall, both in vitro and in silico results suggest that PPO interferes with microbial cell attachment and EPS formation, thereby preventing biofilm colonization.

Investigating the multitargeted anti-diabetic potential of cucurbitane-type triterpenoid from Momordica charantia: an LC-MS, docking-based MM\GBSA and MD simulation study.

Type 2 diabetes accounts for the largest percentage of all diabetic cases worldwide. Cucurbitane-type triterpenes are mainly found in Momordica charantia and possess excellent pharmacological activities. This study was designed to identify cucurbitane-type triterpene from Momordica charantia using Liquid Chromatography-Mass Spectrometry (LC-MS) analysis, examine its anti-diabetic property with molecular docking against diabetes enzymes (alpha-amylase, alpha-glucosidase, dipeptidyl dipeptidase IV and peroxisome proliferator-activated receptor gamma). The stability and interactions of the docked complexes were investigated using molecular dynamics simulation, while the pharmacokinetic and toxicity profile of the ligand was examined using an ADMET server. (23E)-Cucurbita-5,23,25-triene-3,7-dione (CUB) was identified from the LC-MS profiling of the methanolic extract of M. charantia. The molecular docking studies showed that the identified phytochemical elicited good binding energy against all the target receptors. The RMSD and RMSF plots obtained from the 100 ns molecular dynamics simulation showed that the ligand was stable and established substantial interactions with the amino acid residues of the diabetes enzymes which were confirmed by the MM\GBSA computations. The pharmacokinetic and toxicity properties of the ligand showed it was safer as an anti-diabetic drug candidate. Extensive isolation, in vitro and in vivo studies of the ligand against the diabetic enzymes is recommended.Communicated by Ramaswamy H. Sarma.

In-silico analysis reveals Quinic acid as a multitargeted inhibitor against Cervical Cancer.

The cervix is the lowermost part of the uterus that connects to the vagina, and cervical cancer is a malignant cervix tumour. One of this cancer's most important risk factors is HPV infection. In the approach to finding an effective treatment for this disease, various works have been done around genomics and drug discovery. Finding the major altered genes was one of the most significant studies completed in the field of cervical cancer by TCGA (The Cancer Genome Atlas), and these genes are TGFBR2, MED1, ERBB3, CASP8, and HLA-A. The greatest genomic alterations were found in the PI3K/MAPK and TGF-Beta signalling pathways, suggesting that numerous therapeutic targets may come from these pathways in the future. We, therefore, conducted a combined enrichment analysis of genes gathered from various works of literature for this study. The final six key genes from the list were obtained after enrichment analysis using GO, KEGG, and Reactome methods. The six proteins against the identified genes were then subjected to a docking-based screening against a library of 6,87,843 prepared natural compounds from the ZINC15 database. The most stable compound was subsequently discovered through virtual screening to be the natural substance Quinic acid, which also had the highest binding affinity for all six proteins and a better docking score. To examine their stability, the study was extended to MM/GBSA and MD simulations on the six docked proteins, and comparative docking-based calculations led us to identify the Quinic Acid as a multitargeted compound. The overall deviation of the compound was less than 2 Å for all the complexes considered best for the biological molecules, and the simulation interaction analysis reveals a huge web of interaction during the simulation.Communicated by Ramaswamy H. Sarma.

Macrophage-Targeted Punicalagin Nanoengineering to Alleviate Methotrexate-Induced Neutropenia: A Molecular Docking, DFT, and MD Simulation Analysis.

Punicalagin is the most bioactive pomegranate polyphenol with high antioxidant and free-radical scavenging activity and can potentially cure different ailments related to the cardiovascular system. The current research work was envisioned to predict the targeting efficiency of punicalagin (PG) nanoparticles to the macrophages, more specifically to bone marrow macrophages. For this, we selected mannose-decorated PLGA-punicalagin nanoparticles (Mn-PLGA-PG), and before formulating this nanocarrier in laboratory settings, we predicted the targeting efficiency of this nanocarrier by in silico analysis. The analysis proceeded with macrophage mannose receptors to be acquainted with the binding affinity and punicalagin-based nanocarrier interactions with this receptor. In silico docking studies of macrophage mannose receptors and punicalagin showed binding interactions on its surface. PG interacted with hydrogen bonds to the charged residue ASP668 and GLY666 and polar residue GLN760 of the Mn receptor. Mannose with a docking score of -5.811 Kcal/mol interacted with four hydrogen bonds and the mannose receptor of macrophage, and in PLGA, it showed a -4.334 Kcal/mol docking score. Further, the analysis proceeded with density functional theory analysis (DFT) and HOMO-LUMO analysis, followed by an extensive 100 ns molecular dynamics simulation to analyse the trajectories showing the slightest deviation and fluctuation. While analysing the ligand and protein interaction, a wonderful interaction was found among the atoms of the ligand and protein residues. This computational study confirms that this nanocarrier could be a promising lead molecule to regulate the incidence of drug-induced neutropenia. Furthermore, experimental validation is required before this can be stated with complete confidence or before human use.