Evaluation of Senna tora (L.) Roxb. leaves as source of bioactive molecules with antioxidant, anti-inflammatory and antibacterial potential.

Senna tora (L.) Roxb. is an ethno-medicinal herb used by rural and tribal people of the Satpura region of Madhya Pradesh in India and the Phatthalung Province of Thailand for treating rheumatism, bronchitis, ringworm, itches, leprosy, dyspepsia, liver disorders and heart disorders. It is also used in Chinese and Ayurvedic medicine. This study was conducted to investigate the potential of Senna tora (L.) Roxb. as a source of drug candidates against oxidants, inflammation, and bacterial infection. Preliminary phytochemical screening (PPS) and GC-MS were performed to identify the phytochemicals in the ethyl acetate extract of Senna tora (L.) Roxb. leaves (EAESTL). The in vitro antioxidant activity was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH)- and H2O2-scavenging tests; the in vitro anti-inflammatory activity was determined by bovine serum albumin (BSA) denaturation and red blood cell (RBC) hemolysis inhibition; and the antibacterial activity was evaluated by agar-well diffusion methods. Cytotoxicity was estimated by Artemia salina larvae lethality, while acute toxicity was evaluated by oral delivery of the extract to mice. In silico antioxidant, anti-inflammatory, and antibacterial activities were predicted by the Prediction of Activity Spectra for Substances (PASS) program. The pharmacokinetics related to ADME and toxicity tests were determined by the admetSAR2 and ADMETlab2 web servers, and drug-able properties were assessed by the SwissADME server. GC-MS detected fifty-nine phytochemicals that support the types of compounds (phenols, flavonoids, tannins, terpenoids, saponins, steroids, alkaloids, glycosides and reducing sugar) identified by phytochemical screening. EAESTL exhibited dose-dependent antioxidant, anti-inflammatory, and antibacterial activities without any adverse effects or fluctuations in body weight. The PASS program predicted that the identified phytochemicals have antioxidant, anti-inflammatory and antibacterial activities. Among 51 phytochemicals, 16 showed good ADME, and 8 fulfilled drug-able properties without toxicity. Altogether, four phytochemicals, viz., benzyl alcohol, 3-(hydroxy-phenyl-methyl)-2,3-dimethyl-octan-4-one, phenylethyl alcohol and 2,6,6-trimethylbicyclo [3.1.1] heptane-3-ol, showed good pharmacokinetics and drug-able properties without toxicity, along with antioxidant, anti-inflammatory, and antibacterial activities. The obtained results suggest that Senna tora (L.) Roxb. leaves contain bioactive phytochemicals that have the potential to fight against oxidants, inflammation, and bacterial infection as potential drug candidates.

Toward the Identification of Natural Antiviral Drug Candidates against Merkel Cell Polyomavirus: Computational Drug Design Approaches.

Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between -6.5 and -7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.

Curcuma longa L. Prevents the Loss of ß-Tubulin in the Brain and Maintains Healthy Aging in Drosophila melanogaster.

Loss of tubulin is associated with neurodegeneration and brain aging. Turmeric (Curcuma longa L.) has frequently been employed as a spice in curry and traditional medications in the Indian subcontinent to attain longevity and better cognitive performance. We aimed to evaluate the unelucidated mechanism of how turmeric protects the brain to be an anti-aging agent. D. melanogaster was cultured on a regular diet and turmeric-supplemented diet. ß-tubulin level and physiological traits including survivability, locomotor activity, fertility, tolerance to oxidative stress, and eye health were analyzed. Turmeric showed a hormetic effect, and 0.5% turmeric was the optimal dose in preventing aging. ß-tubulin protein level was decreased in the brain of D. melanogaster upon aging, while a 0.5% turmeric-supplemented diet predominantly prevented this aging-induced loss of ß-tubulin and degeneration of physiological traits as well as improved ß-tubulin synthesis in the brain of D. melanogaster early to mid-age. The higher concentration (≥ 1%) of turmeric-supplemented diet decreased the ß-tubulin level and degenerated many of the physiological traits of D. melanogaster. The turmeric concentration-dependent increase and decrease of ß-tubulin level were consistent with the increment and decrement data obtained from the evaluated physiological traits. This correlation demonstrated that turmeric targets ß-tubulin and has both beneficial and detrimental effects that depend on the concentration of turmeric. The findings of this study concluded that an optimal dosage of turmeric could maintain a healthy neuron and thus healthy aging, by preventing the loss and increasing the level of ß-tubulin in the brain.

Spike protein recognizer receptor ACE2 targeted identification of potential natural antiviral drug candidates against SARS-CoV-2.

Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.

Pharmacophore-Based Virtual Screening, Quantum Mechanics Calculations, and Molecular Dynamics Simulation Approaches Identified Potential Natural Antiviral Drug Candidates against MERS-CoV S1-NTD.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >-9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.

Pharmacoinformatics and molecular dynamics simulation-based phytochemical screening of neem plant (Azadiractha indica) against human cancer by targeting MCM7 protein.

Minichromosome maintenance complex component 7 (MCM7) belongs to the minichromosome maintenance family that is important for the initiation of eukaryotic DNA replication. Overexpression of the MCM7 protein is relative to cellular proliferation and responsible for aggressive malignancy in various cancers. Mechanistically, inhibition of MCM7 significantly reduces the cellular proliferation associated with cancer. To date, no effective small molecular candidate has been identified that can block the progression of cancer induced by the MCM7 protein. Therefore, the study has been designed to identify small molecular-like natural drug candidates against aggressive malignancy associated with various cancers by targeting MCM7 protein. To identify potential compounds against the targeted protein a comprehensive in silico drug design including molecular docking, ADME (Absorption, Distribution, Metabolism and Excretion), toxicity, and molecular dynamics (MD) simulation approaches has been applied. Seventy phytochemicals isolated from the neem tree (Azadiractha indica) were retrieved and screened against MCM7 protein by using the molecular docking simulation method, where the top four compounds have been chosen for further evaluation based on their binding affinities. Analysis of ADME and toxicity properties reveals the efficacy and safety of the selected four compounds. To validate the stability of the protein-ligand complex structure MD simulations approach has also been performed to the protein-ligand complex structure, which confirmed the stability of the selected three compounds including CAS ID:105377-74-0, CID:12308716 and CID:10505484 to the binding site of the protein. In the study, a comprehensive data screening process has performed based on the docking, ADMET properties, and MD simulation approaches, which found a good value of the selected four compounds against the targeted MCM7 protein and indicates as a promising and effective human anticancer agent.

Methanol, ethyl acetate and n-hexane extracts of Tragia involucrata L. leaves exhibit anxiolytic, sedative and analgesic activity in Swiss albino mice.

INTRODUCTION: Tragia involucrata L. have been utilized as traditional medicine in Indian subcontinent for the treatment of numerous illnesses such as inflammation, pain and skin infection. In this current study we sought to assess the anxiolytic, sedative and analgesic activity of Tragia involucrata L. leaves extract. MATERIALS AND METHODS: We first performed a phytochemical screening test of the leaves extracts following standard phytochemical screening protocols. We next examined the anxiolytic and sedative activity of crude methanol (TIME), ethyl acetate (TIEAE) and n-Hexane (TIHE) extract of Tragia involucrata L. leaves using mouse behavioral models such as elevated plus-maze test and pentobarbital-induced sleeping time test, respectively. Likewise, we evaluated the analgesic activity using acetic acid induced writhing test and formalin induced paw licking test. Additionally, we performed a quantitative analysis of heavy metals content of Tragia involucrata L. leaves by overnight digestion in concentrated nitric acid (HNO3). RESULTS: Phytochemical screening demonstrated that TIME, TIEAE and TIHE contain flavonoids, alkaloids, tannins, phenols, terpenoids and sterols. Administration of these extracts resulted in higher number of open arm entry, lower number of close arm entry and higher time spent in open arm compared to control treatment (p < 0.05). Moreover, these treatments decreased the onset of sleep time and increased the duration of sleep compared to control treated mice (all p < 0.05). Likewise, extracts treated mice exhibited decreased number of writhing as well as lower acute phase and late phase duration compared to control treatment (all p < 0.05). The average level of As and Fe in Tragia involucrata L. leaves was 5.16 ± 0.012 ppm and 2.76 ± 0.015 ppm, respectively. CONCLUSION: Results from this study support that Tragia involucrata L. leaves extracts exhibit an anxiolytic, sedative and analgesic activity in mice.