Greener approach for the isolation of oleanolic acid from Nepeta leucophylla Benth. Its derivatization and their molecular docking as antibacterial and antiviral agents.

In the present study bioactive methanolic extract along with chloroform and hexane extracts obtained from shade dried leaves of the Himalayan aromatic medicinal plant Nepeta leucophylla Benth. Were screened for the presence of triterpenoids, especially oleanolic acid (OA). Total three compounds oleanolic acid, squalene and linoleic methyl ester were isolated from methanol extract. The percentage yield of OA was 0.11%. Out of these three, OA is more bioactive and was further subjected to derivatization using greener Ultrasonication method. Total three derivatives (3-Acetyl oleanolic acid, 3-Phthaloyl oleanolic acid and 3-Oxo oleanolic acid) were synthesized with 91.16%, 93.98%, and 83.6% respectively. Further, the antioxidant potential of OA and its derivatives were evaluated using DPPH assay which suggested that the 3-Phthaloyl oleanolic acid exhibits highest antioxidant potential with 40.83 ± 1.14% inhibition. OA and its derivatives were screened in-silico antibacterial potential against three bacterial pathogens (E-coli, M. tuberculosis and S. aureus) and antiviral potential against Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), Human immunodeficiency virus (HIV) and H1N1 influenza virus. The in-silico results suggested that 3-phthaloyl oleanolic acid showed best H-bonding with FtsA (Staphylococcus aureus), enoyl acyl reductase (E. coli) and arabinosyl transferase (Mycobactrium tuberculosis). 3-Phthaloyl oleanolic acid also showed best H-Bond interactions with the target proteins hemagglutinin (H1N1) and reverse transcriptase (HIV), whereas, oleanolic acid exhibited the best interactions with RNA dependent RNA polymerase (SARS-CoV-2) and thus could be considered for further in vitro studies.

Antiviral compound screening, peptide designing, and protein network construction of influenza a virus (strain a/Puerto Rico/8/1934 H1N1).

Plant-based antiviral therapy is the current need for holistic health care management, which can be achieved through screening of phytochemicals and designing of antiviral peptides. There exist certain host's factors which are directly involved for rapid viral replication causing worldwide pandemic. A total of 177 phytochemicals from Ocimum sanctum (L.), Tinospora cordifolia (Thunb.) Miers, Cinnamomum camphora (L.) J. Presl., Allium sativum (L.), Curcuma longa (L.), and Aloe vera (L.) Burm. f. were evaluated for their affinity to all viral proteins of H1N1. Applying drug filters and keeping the threshold of such filters relative to the standards, 82 compounds were found suitable for further analysis. Consensus scoring system was used for screening top ligands from 82 compounds, which screened the top 12 compounds. Highly conserved regions (>80%) which were hydrophilic, flexible, antigenic, and also charged were screened out as potent antiviral peptides. The viral proteins were taken as the targets for the modeled peptides for protein-protein docking. Further, host-pathogen interacting network was constructed to unveil host factors involved in viral replication, from which unique protein clusters representing their involvement in viral reproduction were selected through mapping with pathway databases. Twelve compounds and five peptides were found to be highly effective against all the proteins of H1N1. Based on the uniqueness, 13 clusters of proteins were obtained which are engaged in cellular process, namely, viral reproduction, fructose-6-phosphate metabolism, nitrogen compound metabolism, biosynthesis, cellular process, oligodendrocyte development, localization, multiorganism process, primary metabolism, response to unfolded protein, metabolism, and response to protein and catabolism.

Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils.

BACKGROUND: Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO.These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents. MATERIALS AND METHODS: The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3- kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and noncarcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells. RESULTS: The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway. CONCLUSION: Methyl nonanoate, (R)-citronellol, cis-carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile.

Marine steroids as potential anticancer drug candidates: In silico investigation in search of inhibitors of Bcl-2 and CDK-4/Cyclin D1.

Star fishes (Asteroidea) are rich in polar steroids with diverse structural characteristics. The structural modifications of star fish steroids occur at 3ß, 4ß, 5α, 6α (or ß), 7α (or ß), 8, 15α (or ß) and 16ß positions of the steroidal nucleus and in the side chain. Widely found polar steroids in starfishes include polyhydroxysteroids, steroidal sulfates, glycosides, steroid oligoglycosides etc. Bioactivity of these steroids is less studied; only a few reports like antibacterial, cytotoxic activity etc. are available. In continuation of our search for bioactive molecules from natural sources, we undertook in silico screening of steroids from star fishes against Bcl-2 and CDK-4/Cyclin D1 - two important targets of progression and proliferation of cancer cells. We have screened 182 natural steroids from star fishes occurring in different parts of the world and their 282 soft-derivatives by in silico methods. Their physico-chemical properties, drug-likeliness, binding potential with the selected targets, ADMET (absorption, distribution, metabolism, toxicity) were predicted. Further, the results were compared with those of existing steroidal and non steroidal drugs and inhibitors of Bcl-2 and CDK-4/Cyclin D1. The results are promising and unveil that some of these steroids can be potent leads for cancer treatments.