Investigating the anti-cancer compounds from Calliandra harrisii for precision medicine in pancreatic cancer via in-silico drug design and GC-MS analysis.

Pancreatic cancer is a fatal illness caused by mutations in multiple genes. Pancreatic cancer damages the organ that helps in digestion, resulting in symptoms including fatigue, bloating, and nausea. The use of medicinal plants has been crucial in the treatment of numerous disorders. The medicinal plant Calliandra Harrisi has been widely exploited for its possibilities in biology and medicine. The current study aimed to assess the biopotential of biologically active substances against pancreatic cancer. The GC-MS data of these phytochemicals from Calliandra Harrisi were further subjected to computational approaches with pancreatic cancer genes to evaluate their potential as therapeutic candidates. Molecular docking analysis revealed that N-[Carboxymethyl] maleamic acid is the leading molecule responsible for protein denaturation inhibition, having the highest binding affinity of 6.8 kJ/mol among all other compounds with KRAS inflammatory proteins. Furthermore, ADMET analysis and Lipinski's rule validation were also performed revealing its higher absorption in the gastrointestinal tract. The results of the hepatotoxicity test demonstrated that phytochemicals are non-toxic, safe to use, and do not cause necrosis, fibrosis, or vacuolar degeneration even at excessive levels. Calliandra Harrisi has phytoconstituents that have a variety of pharmacological uses in consideration.

Gigantol, a promising natural drug for inflammation: a literature review and computational based study.

Gigantol, a bibenzyl compound extracted from various medicinal plants, has shown a number of biological activities, making it an attractive candidate for potential medical applications. This systematic review aims to shed light on gigantol's promising role in inflammation treatment and its underlying mechanisms. Gigantol exhibits potential anti-inflammatory properties in pre-clinical pharmacological test systems. It effectively reduced the levels of pro-inflammatory markers and arachidonic acid metabolites through various pathways, such as NF-κB, AKT, PI3K, and JNK/cPLA2/12-LOX. The in-silico investigations demonstrated that the MMP-13 enzyme served as the most promising target for gigantol with highest binding affinity (docking score = -8.8 kcal/mol). Encouragingly, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of gigantol confirmed its compatibility with the necessary physiochemical, pharmacokinetic, and toxicity properties, bolstering its potential as a drug candidate. Gigantol, with its well-documented anti-inflammatory properties, could be a promising agent for treating inflammation in the near future.

Identifying potential monkeypox virus inhibitors: an in silico study targeting the A42R protein.

Monkeypox (now Mpox), a zoonotic disease caused by the monkeypox virus (MPXV) is an emerging threat to global health. In the time span of only six months, from May to October 2022, the number of MPXV cases breached 80,000 and many of the outbreaks occurred in locations that had never previously reported MPXV. Currently there are no FDA-approved MPXV-specific vaccines or treatments, therefore, finding drugs to combat MPXV is of utmost importance. The A42R profilin-like protein of the MPXV is involved in cell development and motility making it a critical drug target. A42R protein is highly conserved across orthopoxviruses, thus A42R inhibitors may work for other family members. This study sought to identify potential A42R inhibitors for MPXV treatment using computational approaches. The energy minimized 3D structure of the A42R profilin-like protein (PDB ID: 4QWO) underwent virtual screening using a library of 36,366 compounds from Traditional Chinese Medicine (TCM), AfroDb, and PubChem databases as well as known inhibitor tecovirimat via AutoDock Vina. A total of seven compounds comprising PubChem CID: 11371962, ZINC000000899909, ZINC000001632866, ZINC000015151344, ZINC000013378519, ZINC000000086470, and ZINC000095486204, predicted to have favorable binding were shortlisted. Molecular docking suggested that all seven proposed compounds have higher binding affinities to A42R (-7.2 to -8.3 kcal/mol) than tecovirimat (-6.7 kcal/mol). This was corroborated by MM/PBSA calculations, with tecovirimat demonstrating the highest binding free energy of -68.694 kJ/mol (lowest binding affinity) compared to the seven shortlisted compounds that ranged from -73.252 to -97.140 kJ/mol. Furthermore, the 7 compounds in complex with A42R demonstrated higher stability than the A42R-tecovirimat complex when subjected to 100 ns molecular dynamics simulations. The protein-ligand interaction maps generated using LigPlot+ suggested that residues Met1, Glu3, Trp4, Ile7, Arg127, Val128, Thr131, and Asn133 are important for binding. These seven compounds were adequately profiled to be potential antivirals via PASS predictions and structural similarity searches. All seven potential lead compounds were scored Pa > Pi for antiviral activity while ZINC000001632866 and ZINC000015151344 were predicted as poxvirus inhibitors with Pa values of 0.315 and 0.215, and Pi values of 0.052 and 0.136, respectively. Further experimental validations of the identified lead compounds are required to corroborate their predicted activity. These seven identified compounds represent solid footing for development of antivirals against MPXV and other orthopoxviruses.

Aromatase inhibitors identified from Saraca asoca to treat infertility in women with polycystic ovary syndrome via in silico and in vivo studies.

Polycystic ovary syndrome (PCOS) is a widely occurring metabolic disorder causing infertility in 70%-80% of the affected women. Saraca asoca, an ancient medicinal herb, has been shown to have therapeutic effects against infertility and hormonal imbalance in women. This study was aimed to identify new aromatase inhibitors from S. asoca as an alternative to the commercially available ones via in silico and in vivo approaches. For this, 10 previously reported flavonoids from S. asoca were chosen and the pharmacodynamic and pharmacokinetic properties were predicted using tools like Autodock Vina, GROMACS, Gaussian and ADMETLab. Of the 10, procyanidin B2 and luteolin showed better interaction with higher binding energy when docked against aromatase (3S79) as compared to the commercial inhibitor letrozole. These two compounds showed higher stability in molecular dynamic simulations performed for 100 ns. Molecular mechanics Poisson-Boltzmann surface analysis indicated that these compounds have binding free energy similar to the commercial inhibitor, highlighting their great affinity for aromatase. Density functional theory analysis revealed that both compounds have a good energy gap, and ADMET prediction exhibited the drug-likeness of the two compounds. A dose-dependent administration of these two compounds on zebrafish revealed that both the compounds, at a lower concentration of 50 µg/ml, significantly reduced the aromatase concentration in the ovarian tissues as compared to the untreated control. Collectively, the in silico and in vivo findings recommend that procyanidin B2 and luteolin could be used as potential aromatase inhibitors for overcoming infertility in PCOS patients with estrogen dominance.Communicated by Ramaswamy H. Sarma.

Molecular structure, vibrational spectral, electron density analysis on linaloe oil and molecular docking efficacy against the therapeutic target on human immunodeficiency virus-1 organism (VIRAL protein).

Natural traditional medicine extensively uses certain terpenes and gives plants their flavor, aroma, and color. Treatments for bacterial infections, malaria, and cardiovascular disorders, anti-inflammatory, promote circulation, and heal wounds. 3,7-Dimethyl-1,6-octadien-3-ol (Linalool) is a naturally occurring monoterpene alcohol with no cycle and is a colorless liquid. Spectral analysis such as UV absorption spectra, NMR for structure determination, and IR and Raman for vibrational analysis. The Quantum mechanical approach uses DFT, ELF, and LOL-promolecular electron density, non-relaxed, and atomic density analysis. The biomolecular studies such as molecular dynamics using protein-ligand complex with HIV-1 organism (energy minimization). ADMET for the usage of linalool in different metabolism studies and Molecular docking for binding affinity, its reactive site estimation, and macromolecules that come into contact with protein receptors and conclude ligand binding affinity with protein.

Chemical Composition Antioxidant and Anti-Inflammatory Activities of Myrtus communis L. Leaf Extract: Forecasting ADMET Profiling and Anti-Inflammatory Targets Using Molecular Docking Tools.

Compounds derived from natural sources continue to serve as chemical scaffolds for designing prophylactic/therapeutic options for human healthcare. In this study, we aimed to systematically unravel the chemical profile and antioxidant and anti-inflammatory activities of myrtle methanolic extract (MMEx) using in vitro, in vivo, and in silico approaches. High levels of TPC (415.85 ± 15.52 mg GAE/g) and TFC (285.80 ± 1.64 mg QE/g) were observed. Mass spectrophotometry (GC-MS) analysis revealed the presence of 1,8-cineole (33.80%), α-pinene (10.06%), linalool (4.83%), p-dimethylaminobenzophenone (4.21%), thunbergol (4%), terpineol (3.60%), cis-geranyl acetate (3.25%), and totarol (3.30%) as major compounds. MMEx induced pronounced dose-dependent inhibition in all assays, and the best antioxidant activity was found with H2O2, with an IC50 of 17.81 ± 3.67 µg.mL-1. MMEx showed a good anti-inflammatory effect in vivo by limiting the development of carrageenan-induced paw edema. The pharmacokinetic profiles of the active molecules were determined using the SwissADME website, followed by virtual screening against anti-inflammatory targets including phospholipase A2 (PLA-2), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and NF-κB. A pharmacokinetic study revealed that the molecules have good absorption, distribution, and metabolism profiles, with negative organ toxicity. Among the compounds identified by GC-MS analysis, pinostrobin chalcone, cinnamyl cinnamate, hedycaryol, totarol, and p-dimethylaminobenzophenone were observed to have good binding scores, thus appreciable anti-inflammatory potential. Our study reveals that MMEx from Algerian Myrtus communis L. can be considered to be a promising candidate for alleviating many health complaints associated with oxidative stress and inflammation.

An in silico approach to develop potential therapies against Middle East Respiratory Syndrome Coronavirus (MERS-CoV).

A deadly respiratory disease Middle East Respiratory Syndrome (MERS) is caused by a perilous virus known as MERS-CoV, which has a severe impact on human health. Currently, there is no approved vaccine, prophylaxis, or antiviral therapeutics for preventing MERS-CoV infection. Due to its inexorable and integral role in the maturation and replication of the MERS-CoV virus, the 3C-like protease is unavoidly a viable therapeutic target. In this study, 2369 phytoconstituents were enlisted from Japanese medicinal plants, and these compounds were screened against 3C-like protease to identify feasible inhibitors. The best three compounds were identified as Kihadanin B, Robustaflavone, and 3-beta-O- (trans-p-Coumaroyl) maslinic acid, with binding energies of -9.8, -9.4, and -9.2 kcal/mol, respectively. The top three potential candidates interacted with several active site residues in the targeted protein, including Cys145, Met168, Glu169, Ala171, and Gln192. The best three compounds were assessed by in silico technique to determine their drug-likeness properties, and they exhibited the least harmful features and the greatest drug-like qualities. Various descriptors, such as solvent-accessible surface area, root-mean-square fluctuation, root-mean-square deviation, hydrogen bond, and radius of gyration, validated the stability and firmness of the protein-ligand complexes throughout the 100ns molecular dynamics simulation. Moreover, the top three compounds exhibited better binding energy along with better stability and firmness than the inhibitor (Nafamostat), which was further confirmed by the binding free energy calculation. Therefore, this computational investigation could aid in the development of efficient therapeutics for life-threatening MERS-CoV infections.

Phenolic Compound, Antioxidant, Antibacterial, and In Silico Studies of Extracts from the Aerial Parts of Lactuca saligna L.

Medicinal plants are considered a major source for discovering novel effective drugs. To our knowledge, no studies have reported the chemical composition and biological activities of Moroccan Lactuca saligna extracts. In this context, this study aims to characterize the polyphenolic compounds distributed in hydro-methanolic extracts of L. saligna and evaluate their antioxidant and antibacterial activities; in addition, in silico analysis based on molecular docking and ADMET was performed to predict the antibacterial activity of the identified phenolic compounds. Our results showed the identification of 29 among 30 detected phenolic compounds with an abundance of dicaffeoyltartaric acid, luteolin 7-glucoronide, 3,5-di-O-caffeoylquinic acid, and 5-caffeoylquinic acid with 472.77, 224.30, 196.79, and 171.74 mg/kg of dried extract, respectively. Additionally, antioxidant activity assessed by DPPH scavenging activity, ferric reducing antioxidant power (FRAP) assay, and ferrous ion-chelating (FIC) assay showed interesting antioxidant activity. Moreover, the results showed remarkable antibacterial activity against Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, and Listeria monocytogenes with minimum inhibitory concentrations between 1.30 ± 0.31 and 10.41 ± 0.23 mg/mL. Furthermore, in silico analysis identified three compounds, including Apigenin 7-O-glucuronide, Quercetin-3-O-glucuronide, and 3-p-Coumaroylquinic acid as potent candidates for developing new antibacterial agents with acceptable pharmacokinetic properties. Hence, L. saligna can be considered a source of phytochemical compounds with remarkable activities, while further in vitro and in vivo studies are required to explore the main biological activities of this plant.

In vitro antimicrobial and antioxidant activities, essential oil composition, and in silico molecular modeling analysis of secondary metabolites from roots of Verbascum sinaiticum.

Verbascum sinaiticum is locally used to treat wound, stomachache, viral infection, cancer, sunstroke fever, abdominal colic, diarrhea, hemorrhage, anthrax, and hepatitis. The objective of this study was to identify the compounds and to evaluate the antimicrobial and antioxidant activity of the extracts and isolated compounds from V. sinaiticum. The 1H-NMR, 13C-NMR, and DEPT-135 were used to elucidate the structures of isolated compounds. Essential oils were extracted by hydrodistillation method and their chemical analyses were performed by GC-MS. The broth microdilution method was used to evaluate the antimicrobial activity. The radical scavenging activity of the extracts and isolated compounds were evaluated using DPPH method. Silica gel column chromatographic separation of root extracts afforded seven known compounds: 3'-(4''-methoxy phenyl)-3'-oxo-propionyl hexadecanoate (1), harpagoside (2), pulverulentoside I (3), scrophuloside B4 (4), scropolioside A (5), scropolioside-D2 (6), and harpagide 6-O-ß-glucoside (7), which are all reported from this species for the first time. The EO extracts from leaves and roots were the most susceptible to Streptococcus agalactiae, with a 2 mg/mL MIC. The EO from roots was effective against Candida albicans and Trichophyton mentagrophytes, with a MIC of 8 mg/mL. The MeOH and CH2Cl2/CH3OH (1:1) root extracts showed the maximum activity against S. epidermidis with MIC values of 0.25 mg/mL. The strongest antibacterial effects were demonstrated against Staphylococcus epidermidis, which exhibited a 0.0625 mg/mL MIC for compound 1. The strongest radical scavenging activity was exhibited by the methanol extract (IC50 = 3.4 µg/mL), and compounds 4, 6, 5, 3, 7, and 2 with IC50 values of 3.2, 3.38, 3.6, 3.8, 4.2, and 4.7 µg/mL, respectively, in comparison with ascorbic acid (IC50 = 1.3 µg/mL). The results of the molecular docking analysis of compounds revealed minimal binding energies range from -38.5 to -43.1 kJ/mol, -33.1 to -42.7 kJ/mol, -34.7 to -39.3.7 kJ/mol, -25.5 to -37.6 kJ/mol against human myeloperoxidase (PDB ID: 1DNU), murA enzyme (PDB ID: 1UAE), human topoisomerase IIß (PDB ID: 4fm9), S. epidermidis FtsZ (PDB number: 4M8I) proteins, respectively. The docking results and the in vitro antibacterial activity are in good agreement. These findings show that the isolated compounds 2-7 can act as potential antioxidants and strong antibacterials against Staphylococcus aureus and S. epidermidis. As a result, V. sinaiticum root extracts have the potential to be effective in treating diseases caused by bacteria and free radicals, as long as further investigation has been suggested for the ultimate decision of this plant's potential candidate.

Pharmacokinetics and drug-likeness of anti-cancer traditional Chinese medicine: molecular docking and molecular dynamics simulation study.

MCM7 (Minichromosome Maintenance Complex Component 7) is a component of the DNA replication licensing factor, which controls DNA replication. The MCM7 protein is linked to tumor cell proliferation and has a function in the development of several human cancers. Several types of cancer may be treated by inhibiting the protein, as it is strongly produced throughout this process. Significantly, Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant use against cancer, is rapidly gaining traction as a valuable medical resource for the development of novel cancer therapies, including immunotherapy. Therefore, the goal of the research was to find small molecular therapeutic candidates against the MCM7 protein that may be used to treat human cancers. A computational-based virtual screening of 36,000 natural TCM libraries is carried out for this goal using a molecular docking and dynamic simulation technique. Thereby, ∼8 novel potent compounds i.e., ZINC85542762, ZINC95911541, ZINC85542617, ZINC85542646, ZINC85592446, ZINC85568676, ZINC85531303, and ZINC95914464 were successfully shortlisted, each having the capacity to penetrate the cell as potent inhibitors for MCM7 to curb this disorder. These selected compounds were found to have high binding affinities compared to the reference (AGS compound) i.e. < -11.0 kcal/mol. ADMET and pharmacological properties showed that none of these 8 compounds poses any toxic property (carcinogenicity) and have anti-metastatic, and anticancer activity. Additionally, MD simulations were run to assess the compounds' stability and dynamic behavior with the MCM7 complex for about 100 ns. Finally, ZINC95914464, ZINC95911541, ZINC85568676, ZINC85592446, ZINC85531303, and ZINC85542646 are identified as highly stable within the complex throughout the 100 ns simulations. Moreover, the results of binding free energy suggested that the selected virtual hits significantly bind to the MCM7 which implied these compounds may act as a potential MCM7 inhibitor. However, in vitro testing protocols are required to further support these results. Further, assessment through various lab-based trial methods can assist with deciding the action of the compound that will give options in contrast to human cancer immunotherapy.Communicated by Ramaswamy H. Sarma.

Identification of starvation-mimetic bioactive phytocomponent from Withania somnifera using in-silico molecular modelling and flow cytometry-based analysis for the management of malaria.

Multidrug resistance episodes in malaria increased from 3.9% to 20% from 2015 to 2019. Synchronizing the clinical manifestation in chronological sequence led to a unique impression on glucose demand (increased up to 100-fold) by the parasite-infected RBCs. Hence, restriction in the glucose uptake to parasite-infected RBCs could be an alternative approach to conquer the global burden of malaria to a greater extent. A C28 steroidal lactone Withaferin A (WS-3) isolated from Withania somnifera leave extract shows better thermodynamically stable interactions with the glucose transporters (GLUT-1 and PfHT) to standard drugs metformin and lopinavir. MD simulations for a trajectory period of 100 ns reflect stable interactions with the interactive amino acid residues such as Pro141, Gln161, Gln282, Gln283, Trp388, Phe389, and Phe40, Asn48, Phe85, His168, Gln169, Asn311 which potentiating inhibitory activity of WS-3 against GLUT-1 and PfHT respectively. WS-3 was non-hemotoxic (%hemolysis <5%) for a high concentration of up to 1 mg/ml in the physiological milieu. However, the %hemolysis significantly increased up to 30.55 ± 0.929% in a parasitophorous simulated environment (pH 5.0). Increased hemolysis of WS-3 could be due to the production of ROS in an acidic environment. Further, the inhibitory activity of WS-3 against both glucose transporters was supported with flow cytometry-based analysis of parasite-infected RBCs. Results show that WS-3 has low mean fluorescence intensities for both target proteins compared to conventional drugs, suggesting a potential sugar transporter inhibitor against GLUT-1 and PfHT for managing malaria. Communicated by Ramaswamy H. Sarma.

Pan-genome mediated therapeutic target mining in Kingella kingae and inhibition assessment using traditional Chinese medicinal compounds: an informatics approach.

Kingella kingae causes bacteremia, endocarditis, osteomyelitis, septic arthritis, meningitis, spondylodiscitis, and lower respiratory tract infections in pediatric patients. Usually it demonstrates disease after inflammation of mouth, lips or infections of the upper respiratory tract. To date, therapeutic targets in this bacterium remain unexplored. We have utilized a battery of bioinformatics tools to mine these targets in this study. Core genes were initially inferred from 55 genomes of K. kingae and 39 therapeutic targets were mined using an in-house pipeline. We selected aroG product (KDPG aldolase) involved in chorismate pathway, for inhibition analysis of this bacterium using lead-like metabolites from traditional Chinese medicinal plants. Pharmacophore generation was done using control ZINC36444158 (1,16-bis[(dihydroxyphosphinyl)oxy]hexadecane), followed by molecular docking of top hits from a library of 36,000 compounds. Top prioritized compounds were ZINC95914016, ZINC33833283 and ZINC95914219. ADME profiling and simulation of compound dosing (100 mg tablet) was done to infer compartmental pharmacokinetics in a population of 300 individuals in fasting state. PkCSM based toxicity analysis revealed the compounds ZINC95914016 and ZINC95914219 as safe and with almost similar bioavailability. However, ZINC95914016 takes less time to reach maximum concentration in the plasma and shows several optimal parameters compared to other leads. In light of obtained data, we recommend this compound for further testing and induction in experimental drug design pipeline.Communicated by Ramaswamy H. Sarma.

Repurposing immune boosting and anti-viral efficacy of Parkia bioactive entities as multi-target directed therapeutic approach for SARS-CoV-2: exploration of lead drugs by drug likeness, molecular docking and molecular dynamics simulation methods.

The COVID-19 pandemic has caused adverse health (severe respiratory, enteric and systemic infections) and environmental impacts that have threatened public health and the economy worldwide. Drug repurposing and small molecule multi-target directed herbal medicine therapeutic approaches are the most appropriate exploration strategies for SARS-CoV-2 drug discovery. This study identified potential multi-target-directed Parkia bioactive entities against SARS-CoV-2 receptors (S-protein, ACE2, TMPRSS2, RBD/ACE2, RdRp, MPro, and PLPro) using ADMET, drug-likeness, molecular docking (AutoDock, FireDock and HDOCK), molecular dynamics simulation and MM-PBSA tools. One thousand Parkia bioactive entities were screened out by virtual screening and forty-five bioactive phytomolecules were selected based on favorable binding affinity and acceptable pharmacokinetic and pharmacodynamics properties. The binding affinity values of Parkia phyto-ligands (AutoDock: -6.00--10.40 kcal/mol; FireDock: -31.00--62.02 kcal/mol; and HDOCK: -150.0--294.93 kcal/mol) were observed to be higher than the reference antiviral drugs (AutoDock: -5.90--9.10 kcal/mol; FireDock: -35.64--59.35 kcal/mol; and HDOCK: -132.82--211.87 kcal/mol), suggesting a potent modulatory action of Parkia bioactive entities against the SARS-CoV-2. Didymin, rutin, epigallocatechin gallate, epicatechin-3-0-gallate, hyperin, ursolic acid, lupeol, stigmasta-5,24(28)-diene-3-ol, ellagic acid, apigenin, stigmasterol, and campesterol strongly bound with the multiple targets of the SARS-CoV-2 receptors, inhibiting viral entry, attachment, binding, replication, transcription, maturation, packaging and spread. Furthermore, ACE2, TMPRSS2, and MPro receptors possess significant molecular dynamic properties, including stability, compactness, flexibility and total binding energy. Residues GLU-589, and LEU-95 of ACE2, GLN-350, HIS-186, and ASP-257 of TMPRSS2, and GLU-14, MET-49, and GLN-189 of MPro receptors contributed to the formation of hydrogen bonds and binding interactions, playing vital roles in inhibiting the activity of the receptors. Promising results were achieved by developing multi-targeted antiviral Parkia bioactive entities as lead and prospective candidates under a small molecule strategy against SARS-CoV-2 pathogenesis. The antiviral activity of Parkia bioactive entities needs to be further validated by pre-clinical and clinical trials.

Screening of potential phytomolecules against MurG as drug target in nosocomial pathogen Pseudomonas aeruginosa: perceptions from computational campaign.

The nosocomial infection outbreak caused by Pseudomonas aeruginosa remains a public health concern. Multi-drug resistant (MDR) strains of P. aeruginosa are rapidly spreading leading to a huge mortality rate because of the unavailability of promising antimicrobials. MurG glycotransferase [UDP-N-acetylglucosamine-N-acetylmuramyl (pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase] is located at the plasma membrane and plays a key role in murein (peptidoglycan) biosynthesis in bacteria. Since MurG is required for bacterial cell wall synthesis and is non-homologous to Homo sapiens; it can be a potential target for the antagonist to treat P. aeruginosa infection. The discovery of high-resolution crystal structure of P. aeruginosa MurG offers an opportunity for the computational identification of its prospective inhibitors. Therefore, in the present study, the crystal structure of MurG (PDB ID: 3S2U) from P. aeruginosa was selected, and computational docking analyses were performed to search for functional inhibitors of MurG. IMPPAT (Indian medicinal plants, phytochemicals and therapeutic) phytomolecule database was screened by computational methods with MurG catalytic site. Docking results identified Theobromine (-8.881 kcal/mol), demethoxycurcumin (-8.850 kcal/mol), 2-alpha-hydroxycostic acid (-8.791 kcal/mol), aurantiamide (-8.779 kcal/mol) and petasiphenol (-8.685 kcal/mol) as a potential inhibitor of the MurG activity. Further, theobromine and demethoxycurcumin were subjected to MDS (molecular dynamics simulation) and free energy (MM/GBSA) analysis to comprehend the physiological state and structural stability of MurG-phytomolecules complexes. The outcomes suggested that these two phytomolecules could act as most favorable natural hit compounds for impeding the enzymatic action of MurG in P. aeruginosa, and thus it needs further validation by both in vitro and in vivo analysis. HIGHLIGHTSThe top phytomolecules such as theobromine, demethoxycurcumin, 2-alpha-hydroxycostic acid, aurantiamide and petasiphenol displayed promising binding with MurG catalytic domain.MurG complexed with theobromine and demethoxycurcumin showed the best interaction and stable by MD simulation at 100 ns.The outcome of MurG binding phytomolecules has expanded the possibility of hit phytomolecules validation.Communicated by Ramaswamy H. Sarma.

Antifungal Constituents of Piper crocatum and Their Activities as Ergosterol Biosynthesis Inhibitors Discovered via In Silico Study Using ADMET and Drug-Likeness Analysis.

Along with the increasing resistance of Candida spp. to some antibiotics, it is necessary to find new antifungal drugs, one of which is from the medicinal plant Red Betel (Piper crocatum). The purpose of this research is to isolate antifungal constituents from P. crocatum and evaluate their activities as ergosterol biosynthesis inhibitors via an in silico study of ADMET and drug-likeness analysis. Two new active compounds 1 and 2 and a known compound 3 were isolated, and their structures were determined using spectroscopic methods, while their bioactivities were evaluated via in vitro and in silico studies, respectively. Antifungal compound 3 was the most active compared to 1 and 2 with zone inhibition values of 14.5, 11.9, and 13.0 mm, respectively, at a concentration of 10% w/v, together with MIC/MFC at 0.31/1.2% w/v. Further in silico study demonstrated that compound 3 had a stronger ΔG than the positive control and compounds 1 and 2 with -11.14, -12.78, -12.00, and -6.89 Kcal/mol against ERG1, ERG2, ERG11, and ERG24, respectively, and also that 3 had the best Ki with 6.8 × 10-3, 4 × 10-4, 1.6 × 10-3, and 8.88 µM. On the other hand, an ADMET analysis of 1-3 met five parameters, while 1 had one violation of Ro5. Based on the research data, the promising antifungal constituents of P. crocatum allow P. crocatum to be proposed as a new antifungal candidate to treat and cure infections due to C. albicans.

Antidiabetic Activity, Molecular Docking, and ADMET Properties of Compounds Isolated from Bioactive Ethyl Acetate Fraction of Ficus lutea Leaf Extract.

Diabetes contributes to the rising global death rate. Despite scientific advancements in understanding and managing diabetes, no single therapeutic agent has been identified to effectively treat and prevent its progression. Consequently, the exploration for new antidiabetic therapeutics continues. This study aimed to investigate the antidiabetic bioactive ethyl acetate fraction of F. lutea at the molecular level to understand the molecular interactions and ligand-protein binding. To do this, the fraction underwent column chromatography fractionation to yield five compounds: lupeol, stigmasterol, α-amyrin acetate, epicatechin, and epiafzelechin. These compounds were evaluated in vitro through α-glucosidase inhibition and glucose utilization assays in C2C12 muscle and H-4-11-E liver cells using standard methods. In silico analysis was conducted using molecular docking and ADMET studies. Epicatechin exhibited the most potent α-glucosidase inhibition (IC50 = 5.72 ± 2.7 µg/mL), while epiafzelechin stimulated superior glucose utilization in C2C12 muscle cells (33.35 ± 1.8%) and H-4-11-E liver cells (46.7 ± 1.2%) at a concentration of 250 µg/mL. The binding energies of the isolated compounds for glycogen phosphorylase (1NOI) and α-amylase (1OSE) were stronger (<-8.1) than those of the positive controls. Overall, all tested compounds exhibited characteristics indicative of their potential as antidiabetic agents; however, toxicity profiling predicted epiafzelechin and epicatechin as better alternatives. The ethyl acetate fraction and its compounds, particularly epiafzelechin, showed promise as antidiabetic agents. However, further comprehensive studies are necessary to validate these findings.

In silico screening of herbal phytochemicals to develop a Rasayana for immunity against Nipah virus.

BACKGROUND: The first emergence of the Nipah virus (NiV) in 1998 from Malaysia became a major concern when it came to light and resurfaced on different occasions thereafter. NiV is a bat-borne zoonotic and pleomorphic virus that causes severe infection in human and animal hosts. Studies revealed fruit bats are the major reservoirs as natural hosts and pigs as intermediate hosts for the spread of this infection. This became a major concern as the disease was characterized by high pathogenicity varying from 40% to 80% depending on its acuteness. Moreover, the solemnity lies in the fact that the infection transcends from being a mere mild illness to an acute respiratory infection leading to fatal encephalitis with a reportedly high mortality rate. Currently, there is no treatment or vaccine available against the NiV. Many antiviral drugs have been explored and developed but with limited efficacy. METHODOLOGY: In search of high-affinity ayurvedic alternatives, we conducted a pan-proteome in silico exploration of the NiV proteins for their interaction with the best-suited phytoconstituents. The toxicity prediction of thirty phytochemicals based on their LD50 value identified thirteen potential candidates. Molecular docking studies of those thirteen phytochemicals with five important NiV proteins identified Tanshinone I as the potential compound with a high binding affinity. RESULTS: The pharmacokinetics and pharmacodynamics studies also aided in determining the absorption, distribution, metabolism, excretion, and toxicity of the selected phytoconstituent. Interestingly, docking studies also revealed Rosmariquinone as a potent alternative to the antiviral drug Remdesivir binding the same pocket of RNA-dependent RNA polymerase of the NiV. A molecular dynamics simulation study of the surface glycoprotein of NiV against Tanshinone I showed a stable complex formation and significant allosteric changes in the protein structure, implying that these phytochemicals could be a natural alternative to synthetic drugs against NiV. CONCLUSION: This study provides preliminary evidence based on in silico analysis that the herbal molecules showed an effect against NiV. However, it is essential to further evaluate the efficacy of this approach through cell-based experiments, organoid models, and eventually clinical trials.

Identification of potential anti-hyperglycemic compounds in Cordyceps militaris ethyl acetate extract: in vitro and in silico studies.

Cordyceps militaris has been long known for valuable health benefits by folk experience and was recently reported with diabetes-tackling evidences, thus deserving extending efforts on screening for component-activity relationship. In this study, experiments were carried out to find the evidence, justification, and input for computations on the potential against diabetes-related protein structures: PDB-4W93, PDB-3W37, and PDB-4A3A. Liquid chromatography identified 14 bioactive compounds in the ethyl acetate extract (1-14) and quantified the contents of cordycepin (0.11%) and adenosine (0.01%). Bioassays revealed the overall potential of the extract against α-amylase (IC50 = 6.443 ± 0.364 mg.mL-1) and α-glucosidase (IC50 = 2.580 ± 0.194 mg.mL-1). A combination of different computational platforms was used to select the most promising candidates for applications as anti-diabetic bio-inhibitors, i.e. 1 (ground state: -888.49715 a.u.; dipole moment 3.779 Debye; DS¯ -12.3 kcal.mol-1; polarizability 34.7 Å3; logP - 1.30), 10 (ground state: -688.52406 a.u.; dipole moment 5.487 Debye; DS¯ -12.6 kcal.mol-1; polarizability 24.9 Å3; logP - 3.39), and 12 (ground state: -1460.07276 a.u.; dipole moment 3.976 Debye; DS¯ -12.5 kcal.mol-1; polarizability 52.4 Å3; logP - 4.39). The results encourage further experimental tests on cordycepin (1), mannitol (10), and adenosylribose (12) to validate their in-practice diabetes-related activities, thus conducive to hypoglycemic applications.Communicated by Ramaswamy H. Sarma.

Pterodon emarginatus Seed Preparations: Antiradical Activity, Chemical Characterization, and In Silico ADMET Parameters of ß-caryophyllene and Farnesol.

The study of medicinal plants and their active compounds is relevant to maintaining knowledge of traditional medicine and to the development of new drugs of natural origin with lower environmental impact. From the seeds of the Brazilian plant Pterodon emarginatus, six different preparations were obtained: essential oil (EO), ethanol extract (EthE) prepared using the traditional method, and four extracts using solvents at different polarities, such as n-hexane, chloroform, ethyl acetate, and methanol (HexE, ChlE, EtAE, and MetE). Chemical characterization was carried out with gas chromatography, allowing the identification of several terpenoids as characteristic components. The two sesquiterpenes ß-caryophyllene and farnesol were identified in all preparations of Pterodon emarginatus, and their amounts were also evaluated. Furthermore, the total flavonoid and phenolic contents of the extracts were assessed. Successively, the antiradical activity with DPPH and ORAC assays and the influence on cell proliferation by the MTT test on the human colorectal adenocarcinoma (HT-29) cell line of the preparations and the two compounds were evaluated. Lastly, an in silico study of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) showed that ß-caryophyllene and farnesol could be suitable candidates for development as drugs. The set of data obtained highlights the potential medicinal use of Pterodon emarginatus seeds and supports further studies of both plant preparations and isolated compounds, ß-caryophyllene and farnesol, for their potential use in disease with free radical involvement as age-related chronic disorders.

Phytochemical characterization of Typha domingensis and the assessment of therapeutic potential using in vitro and in vivo biological activities and in silico studies.

Typha domingensis, a medicinal plant with significant traditional importance for curing various human diseases, has potentially bioactive compounds but was less explored previously. Therefore, this study aims to investigate the therapeutic potential of T. domingensis by evaluating the phytochemical profile through high-performance liquid chromatography (HPLC) techniques and its biological activities (in vitro and in vivo) from the methanolic extract derived from the entire plant (TDME). The secondary metabolite profile of TDME regulated by reverse phase ultra-high-performance liquid chromatography-mass spectrometry (RP-UHPLC-MS) revealed some bioactive compounds by -ve and +ve modes of ionization. The HPLC quantification study showed the precise quantity of polyphenols (p-coumaric acid, 207.47; gallic acid, 96.25; and kaempferol, 95.78 µg/g extract). The enzyme inhibition assays revealed the IC50 of TDME as 44.75 ± 0.51, 52.71 ± 0.01, and 67.19 ± 0.68 µgmL-1, which were significant compared to their respective standards (indomethacin, 18.03 ± 0.12; quercetin, 4.11 ± 0.01; and thiourea, 8.97 ± 0.11) for lipoxygenase, α-glucosidase, and urease, respectively. Safety was assessed by in vitro hemolysis (4.25% ± 0.16% compared to triton × 100, 93.51% ± 0.36%), which was further confirmed (up to 10 g/kg) by an in vivo model of rats. TDME demonstrated significant (p < 0.05) potential in analgesic activity by hot plate and tail immersion tests and anti-inflammatory activity by the carrageenan-induced hind paw edema model. Pain latency decreased significantly, and the anti-inflammatory effect increased in a dose-dependent way. Additionally, in silico molecular docking revealed that 1,3,4,5-tetracaffeoylquinic acid and formononetin 7-O-glucoside-6″-O-malonate possibly contribute to enzyme inhibitory activities due to their higher binding affinities compared to standard inhibitors. An in silico absorption, distribution, metabolism, excretion, and toxicological study also predicted the pharmacokinetics and safety of the chosen compounds identified from TDME. To sum up, it was shown that TDME contains bioactive chemicals and has strong biological activities. The current investigations on T. domingensis could be extended to explore its potential applications in nutraceutical industries and encourage the isolation of novel molecules with anti-inflammatory and analgesic effects.