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.

Multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis of the synergistic effects between natural compounds baicalein and cubebin for the inhibition of the main protease of SARS-CoV-2.

Combination drugs have been used for several diseases for many years since they produce better therapeutic effects. However, it is still a challenge to discover candidates to form a combination drug. This study aimed to investigate whether using a comprehensive in silico approach to identify novel combination drugs from a Chinese herbal formula is an appropriate and creative strategy. We, therefore, used Toujie Quwen Granules for the main protease (Mpro) of SARS-CoV-2 as an example. We first used molecular docking to identify molecular components of the formula which may inhibit Mpro. Baicalein (HQA004) is the most favorable inhibitory ligand. We also identified a ligand from the other component, cubebin (CHA008), which may act to support the proposed HQA004 inhibitor. Molecular dynamics simulations were then performed to further elucidate the possible mechanism of inhibition by HQA004 and synergistic bioactivity conferred by CHA008. HQA004 bound strongly at the active site and that CHA008 enhanced the contacts between HQA004 and Mpro. However, CHA008 also dynamically interacted at multiple sites, and continued to enhance the stability of HQA004 despite diffusion to a distant site. We proposed that HQA004 acted as a possible inhibitor, and CHA008 served to enhance its effects via allosteric effects at two sites. Additionally, our novel wavelet analysis showed that as a result of CHA008 binding, the dynamics and structure of Mpro were observed to have more subtle changes, demonstrating that the inter-residue contacts within Mpro were disrupted by the synergistic ligand. This work highlighted the molecular mechanism of synergistic effects between different herbs as a result of allosteric crosstalk between two ligands at a protein target, as well as revealed that using the multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis to discover novel combination drugs from a Chinese herbal remedy is an innovative pathway.

In silico screening of the phytochemicals present in Clitoria ternatea L. as the inhibitors of snake venom phospholipase A2 (PLA2).

Millions of people suffer from snake bite envenomation, and its management is a challenge, even today. Medicinal plants have attracted the researcher's attention for their outstanding advantages in treating many diseases, including snake venom poisoning. Clitoria ternatea L, is a plant popularly known for its various pharmacological effects especially, anti-snake venom property. However, the molecular mechanism behind this is poorly understood. It is reported that snake venom PLA2 is an extensively studied toxic factor. This study is meant to screen the compound's capability to act as inhibitors of the Daboia russelli snake venom PLA2 through molecular docking and dynamics studies. Our results show that among the 27 compounds taken for the study, only Kaempferol showed good interaction profile with the conserved catalytic active site residues, His48 and Asp49. The pharmacophore features of the compound also demonstrate its exact fitting at the binding pocket. Further RMSD, RMSF, Rg, and hydrogen bond analysis confirmed the stable binding of Kaempferol with PLA2 through molecular dynamic simulations for 100 ns. In addition, the MM/PBSA binding free energy calculation of the complex was also affirming the docking results. The binding free energy (BFE) of Kaempferolis better than the reference compound. ADME and Lipinski's rule of five reveals its drug like properties.Communicated by Ramaswamy H. Sarma.

Molecular docking studies of phytochemicals from Terminalia chebula for identification of potential multi-target inhibitors of SARS-CoV-2 proteins.

Background: The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a global pandemic claiming more than 6 million lives worldwide as of 16 March 2022. Till date, no medicine has been developed which is proved to have 100% efficiency in combating against this deadly disease. We focussed on ayurvedic medicines to identify drug-like candidates for treatment and management of COVID-19. Among all ayurvedic medicines, we were interested in Terminalia chebula (T. chebula), as it is known to have antibacterial, antifungal, antiviral, antioxidant and anti-inflammatory properties. Objectives: In this study, we evaluated potential inhibitory effects of phytochemicals from T. chebula against eight structural and functional proteins of SARS-CoV-2. Material and methods: We performed blind molecular docking studies using fifteen phytochemicals from T. chebula against the proteins of SARS-CoV-2. The three-dimensional proteins structures were analysed and potential drug-binding sites were identified. The drug-likeness properties of the ligands were assessed as well. Results: Analysing the docking results by comparing Atomic Contact Energy (ACE) and intermolecular interactions along with assessment of ADME/T properties identified 1,3,6-Trigalloyl glucose (-332.14 ± 55.74 kcal/mol), Beta-Sitosterol (-324.75 ± 36.98 kcal/mol) and Daucosterol (-335.67 ± 104.79 kcal/mol) as most promising candidates which exhibit significantly high inhibition efficiency against all eight protein targets. Conclusions: We believe that our study has the potential to help the scientific communities to develop multi-target drugs from T. chebula to combat against the deadly pathogen of COVID-19, with the support of extensive wet lab analysis.

Isolation, Docking and In Silico ADME-T Studies of Acacianol: Novel Antibacterial Isoflavone Analogue Isolated from Acacia leucophloea Bark.

BACKGROUND: The plant Acacia leucophloea (Roxb.) Willd. of the family Fabaceae is of paramount importance in Indian medicine. OBJECTIVES: We sought to evaluate the in vitro anti-microbial activity of A. leucophloea stem bark extract together with its phytochemical characterization and exploration of drug-likeness attributes. METHODS: In vitro Kirby-Bauer disc-diffusion and tube-dilution assays were exploited for determining the anti-microbial activity of the methanolic bark extracts against several bacterial test strains. Spectral characterization of the isolated phytoconstituents was performed using spectroscopy techniques viz., UV, IR, 1H NMR, and mass spectroscopy followed by the in silico studies like docking and ADME-T studies. RESULTS: The crude methanolic extracts were active against all the bacterial test strains, albeit weakly or moderately, as indicated by the zone of inhibition and minimum inhibitory concentration in the anti-microbial assays. The isolated phytoconstituent was identified to be 3-(3,4-dihydro-5-methoxy-2H-chromen-6-yl)-2,5- dimethoxy-2H-chromen-7-ol (hereby coined as acacianol), a novel isoflavone analog. Acacianol demonstrated a strong binding affinity towards the bacterial DNA gyrase over clorobiocin, especially in the case of cavity 4 with no predicted toxicities in silico, except skin sensitization and chromosome damage.

In-silico Studies and Wet-Lab Validation of Camptothecin Derivatives for Anti-Cancer Activity Against Liver (HepG2) and Lung (A549) Cancer Cell Lines.

BACKGROUND: In the present study, we have explored the utility of QSAR modelling, in silico ADMET, docking, chemical semi-synthesis, and in vitro evaluation studies for the identification of active camptothecin (CPT) derivatives against cancer-targeting human liver (HepG2) and lung (A549) cancer cell lines. METHODS: Two QSAR models were developed as screenings tools using the multiple linear regression (MLR) method followed by ADMET and docking studies. The regression coefficient (r2) and cross-validation regression coefficients (rCV2T) of the QSAR model for the HepG2 cell line was 0.95 and 0.90, respectively, and for the A549 cell line, it was 0.93 and 0.81, respectively. RESULTS: In silico studies show that CPT derivatives (CPT-1 and CPT-6) possess drug-like properties. Docking performed on DNA Topoisomerase-I showed significant binding affinity. Finally, predicted active derivatives were chemically semi synthesized, spectroscopically characterized, and evaluated in-vitro for cytotoxic/anticancer activity against HepG2 and A549 cell lines. CONCLUSION: The experimental results are consistent with the predicted results. These findings may be of immense importance in the anticancer drug development from an inexpensive and widely available natural product, camptothecin.

Insightful Valorization of the Biological Activities of Pani Heloch Leaves through Experimental and Computer-Aided Mechanisms.

Pani heloch (Antidesma montanum) is traditionally used to treat innumerable diseases and is a source of wild vegetables for the management of different pathological conditions. The present study explored the qualitative phytochemicals; quantitative phenol and flavonoid contents; in vitro antioxidant, anti-inflammatory, and thrombolytic effects; and in vivo antipyretic and analgesic properties of the methanol extract of A. montanum leaves in different experimental models. The extract exhibited secondary metabolites including alkaloids, flavonoids, flavanols, phytosterols, cholesterols, phenols, terpenoids, glycosides, fixed oils, emodines, coumarins, resins, and tannins. Besides, Pani heloch showed strong antioxidant activity (IC50 = 99.00 µg/mL), while a moderate percentage of clot lysis (31.56%) in human blood and significant anti-inflammatory activity (p < 0.001) was achieved with the standard. Moreover, the analgesic and antipyretic properties appeared to trigger a significant response (p < 0.001) relative to in the control group. Besides, an in silico study of carpusin revealed favorable protein-binding affinities. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity analysis and toxicological properties of all isolated compounds adopted Lipinski's rule of five for drug-like potential and level of toxicity. Our research unveiled that the methanol extract of A. montanum leaves exhibited secondary metabolites that are a good source for managing inflammation, pyrexia, pain, and cellular toxicity. Computational approaches and further studies are required to identify the possible mechanism which responsible for the biological effects.

Evaluation of Various Solvent Extracts of Tetrastigma leucostaphylum (Dennst.) Alston Leaves, a Bangladeshi Traditional Medicine Used for the Treatment of Diarrhea.

Tetrastigma leucostaphylum (TL) is an important ethnic medicine of Bangladesh used to treat diarrhea and dysentery. Hence, current study has been designed to characterize the antidiarrheal (in vivo) and cytotoxic (in vitro) effects of T. leucostaphylum. A crude extract was prepared with methanol (MTL) and further partitioned into n-hexane (NTL), dichloromethane (DTL), and n-butanol (BTL) fractions. Antidiarrheal activity was investigated using castor oil induced diarrhea, enteropooling, and gastrointestinal transit models, while cytotoxicity was evaluated using the brine shrimp lethality bioassay. In antidiarrheal experiments, all doses (100, 200, and 400 mg/kg) of the DTL extract significantly reduced diarrheal stool frequency, volume and weight of intestinal contents, and gastrointestinal motility in mice. Similarly, in the cytotoxicity assay, all extracts exhibited activity, with the DTL extract the most potent (LC50 67.23 µg/mL). GC-MS analysis of the DTL extract identified 10 compounds, which showed good binding affinity toward M3 muscarinic acetylcholine, 5-HT3, Gut inhibitory phosphodiesterase, DNA polymerase III subunit alpha, and UDP-N-acetylglucosamine-1 carboxyvinyltransferase enzyme targets upon molecular docking analysis. Although ADME/T analyses predicted the drug-likeness and likely safety upon consumption of these bioactive compounds, significant toxicity concerns are evident due to the presence of the known phytotoxin, 2,4-di-tert-butylphenol. In summary, T. leucostaphylum showed promising activity, helping to rationalize the ethnomedicinal use and importance of this plant, its safety profile following both acute and chronic exposure warrants further investigation.

GC-MS Phytochemical Profiling, Pharmacological Properties, and In Silico Studies of Chukrasia velutina Leaves: A Novel Source for Bioactive Agents.

Chukrasia velutina is a local medicinal plant commonly known as chikrassy in Bangladesh, India, China, and other South Asian countries. The leaves, bark, and seeds are vastly used as herbal medicine for fever and diarrhea, and its leaves essential oils are used for antimicrobial purposes. In this study, we discuss the neuropsychiatric properties of C. velutina leaves through several animal models, quantitative and qualitative phytochemical analysis, and computational approaches. Neuropsychiatric effects were performed in rodents on the methanolic extract of C. velutina leaves (MECVL). Antidepressant, anxiolytic, and sedative effects experimented through these rodent models were used such as the force swimming test (FST), tail suspension test (TST), hole board test (HBT), elevated plus maze test (EPMT), light/dark box test (LDBT), open field test (OFT), and hole cross test (HCT). In these rodent models, 200 and 400 mg/kg doses were used which exhibited a significant result in the force swimming and tail suspension test (p < 0.001) for the antidepressant effect. In the anxiolytic study, the results were significant in the hole board, elevated plus maze, and light/dark box test (p < 0.001) for doses of 200 and 400 mg/kg. The result was also significant in the open field and hole cross test (p < 0.001) for sedative action in the sake of similar doses. Moreover, qualitative and quantitative studies were also performed through phytochemical screening and GC-MS analysis, and fifty-seven phytochemical compounds were found. These compounds were analyzed for pharmacokinetics properties using the SwissADME tool and from them, thirty-five compounds were considered for the molecular docking analysis. These phytoconstituents were docking against the human serotonin receptor, potassium channel receptor, and crystal structure of human beta-receptor, where eight of the compounds showed a good binding affinity towards the respective receptors considered to the reference standard drugs. After all of these analyses, it can be said that the secondary metabolite of C. velutina leaves (MECVL) could be a good source for inhibiting the neuropsychiatric disorders which were found on animal models as well as in computational studies.

Intervention in Neuropsychiatric Disorders by Suppressing Inflammatory and Oxidative Stress Signal and Exploration of In Silico Studies for Potential Lead Compounds from Holigarna caustica (Dennst.) Oken leaves.

Holigarna caustica (Dennst.), a popular plant used in folk medicine in Bangladesh, is often used by the local folk practitioner to treat a variety of chronic diseases. The present research is an attempt to find out an innovative therapeutic prospect for the management of neuropsychiatric disorders. The methanol extract of H. caustica leaves (MEHC) were utilized on various behavioral tests for assessing anxiolytic, anti-depressant, and anti-inflammatory activities. The antioxidant potentials and quantitative phytochemicals were evaluated through spectrophotometric methods. Results revealed that treatment of MEHC (200 and 400 mg/kg) significantly reduced anxiety like behaviors in mice, particularly, 400 mg/kg efficiently improved % of entries and time spent (p < 0.05) in the open arms in elevated plus maze test, whereas, superior head dipping tendency (p < 0.05) was observed in hole-board test. In contrast, mice treated with 200 mg/kg revealed better anxiolytic effect in both open field and hole-cross tests. During antidepressant evaluation, mice administrated with MEHC exhibited active behaviors (swimming and struggling) in forced swimming and tail suspension tests. In parallel, MEHC manifested a noteworthy (p < 0.001) suppression of inflammatory response induced by histamine. The MEHC also showed strong antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) (IC50: 57.64 µg/mL) scavenging, H2O2 (IC50: 51.60 µg/mL) scavenging, and ferric reducing power assay. The levels of total phenol, flavonoid, flavonol, condensed tannin, and antioxidant were estimated as higher in MEHC. Moreover, 11 compounds were documented as bioactive, displayed good binding affinities to potassium channel receptor, human serotonin receptor, cyclooxygenase (COX-1 and 2), and xanthine oxidoreductase enzyme targets in molecular docking experiments. Furthermore, ADME/T and Prediction of Activity Spectra for Substances (PASS) analyses exposed their drug-likeness, nontoxic upon consumption, and likely pharmacological actions. Overall, the H. caustica is potentially bioactive as evident by in vivo, in vitro, and computational analysis. Our findings support the folkloric value of this plant, which may provide a potential source towards developing drug leads.

[Pharmacodynamic effect and virulent effect of Tripterygium wilfordii based on network pharmacology].

To investigate the pharmacodynamic effect and virulent effect of the main components of the toxic Chinese medicine Tripterygium wilfordii,such as triptolide,tripchlorolide,tripterine,demethylzeylasteral,wilfotrine and euonine,the admet SAR online assessment system was used to calculate the properties of the main components of T. wilfordii. The potential targets of the components were mined and collected through multiple databases,and the potential targets were enriched by the bioinformatics database DAVID.Cytoscape software was used to establish a " target-pathway" network and perform topology analysis on the network. The main chemical components of T. wilfordii were able to penetrate the blood-brain barrier and had intestinal permeability. A total of 65 targets were predicted,including pathways in cancer,hepatitis B,rheumatoid arthritis,and chagas disease( American trypanosomiasis),Toll-like receptor signaling pathway,apoptosis,colorectal cancer,NF-kappa B signaling pathway,etc. T. wilfordii mainly plays a role in the treatment of immune diseases and cancer by regulating inflammatory signaling pathways and cancer signaling pathways. Its action on apoptosis pathway and drug metabolism enzymes may be the mechanism of its toxicity.

Isovaleric acid and avicequinone-C are Chikungunya virus resistance principles in Glycosmis pentaphylla (Retz.) Correa.

BACKGROUND & OBJECTIVES: Oral administration of tender leaf extract of Glycosmis pentaphylla is traditionally known to prevent the chikungunya virus infection. Even with wide usage, the antiviral components in this plant are neither identified nor characterized. This study was carried out with the objectives of profiling the phytocompounds in this plant through LC-MS/MS and to identify the active antiviral constituents and their drug-likeliness through molecular docking. METHODS: Phytocompounds were extracted hydro-alcoholically from powdered plant parts and analyzed using LC-MS/MS. Based on mass-to-charge ratio from LC-MS/MS, compounds were identified and used as ligands for molecular docking against chikungunya target proteins. The active principles were subjected to ADME/T analysis to verify their drug-likeliness. RESULTS: The docking results and ADME/T evaluation showed that the compounds, isovaleric acid and avicequinone- C have good interaction with the protein targets and hence could be the antiviral principles of the selected plant. These compounds presented acceptable drug properties and hence could be carried forward to in vivo studies for drug development. INTERPRETATION & CONCLUSION: The antiviral properties of G. pentaphylla are known since time-immemorial. This study revealed the probable interactions after the oral administration of tender leaves of Glycosmis in preventing the chikungunya virus infection and paves the path for designing future plant-based drugs.

Pharmacodynamic effect and virulent effect of Tripterygium wilfordii based on network pharmacology / 中国中药杂志

To investigate the pharmacodynamic effect and virulent effect of the main components of the toxic Chinese medicine Tripterygium wilfordii,such as triptolide,tripchlorolide,tripterine,demethylzeylasteral,wilfotrine and euonine,the admet SAR online assessment system was used to calculate the properties of the main components of T. wilfordii. The potential targets of the components were mined and collected through multiple databases,and the potential targets were enriched by the bioinformatics database DAVID.Cytoscape software was used to establish a " target-pathway" network and perform topology analysis on the network. The main chemical components of T. wilfordii were able to penetrate the blood-brain barrier and had intestinal permeability. A total of 65 targets were predicted,including pathways in cancer,hepatitis B,rheumatoid arthritis,and chagas disease( American trypanosomiasis),Toll-like receptor signaling pathway,apoptosis,colorectal cancer,NF-kappa B signaling pathway,etc. T. wilfordii mainly plays a role in the treatment of immune diseases and cancer by regulating inflammatory signaling pathways and cancer signaling pathways. Its action on apoptosis pathway and drug metabolism enzymes may be the mechanism of its toxicity.

In vivo analgesic effect of different extracts of Hopea odorata leaves in mice and in silico molecular docking and ADME/T property analysis of some isolated compounds from this plant.

Background The current study evaluates the analgesic effect of different extracts of Hopea odorata leaves in mice followed by molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) analysis of isolated compounds derived from the plant with the COX-1 enzyme. Methods In the present study, the dried leaves of H. odorata were subjected to extraction using methanol, ethanol, and water. In vivo analgesic activity was evaluated by using the acetic acid-induced writhing test and formalin-induced paw licking test, and in silico molecular docking and ADME/T study were performed using Schrödinger Maestro (version 11.1) and online-based tools, respectively, on eight isolated compounds. Results The results showed that the methanolic extract of leaves has highest significant dose-dependent analgesic activity at both 200 and 400 mg/kg followed by ethanolic extract of leaves. Among all the compounds, ampelopsin showed the best docking score of -7.055, ensuring strong binding affinity between the ligand and the receptor, and ADME/T analysis using Web-based tools ensures the compound has not violated Lipinski's rule of five indicating its safety consumption. Conclusions The result confirms the analgesic activity of H. odorata leaves in both in vivo and in silico assays. The data support ampelopsin to be a potent analgesic compound worthy of future clinical trials and its "drug-likeliness".

Modern Computational Strategies for Designing Drugs to Curb Human Diseases: A Prospect.

Drug discovery is an exhaustive and time-consuming process involving numerous stages like target identification, validation, lead optimization, preclinical trials, clinical trials and finally postmarketing vigilance for drug safety. The application of computer-aided drug designing (CADD) is an indispensable approach for developing safe and effective drugs. Previous methods based on combinatorial chemistry (CC) and high throughput screening (HTS) consumed a lot of time as well as expenditure. CADD based approaches including pharmacophore modeling (PM), molecular docking (MD), inverse docking, chemical similarity (CS), quantitative structure-activity relationship (QSAR), virtual screening (VS) and molecular dynamics simulations have been quite productive in predicting the therapeutic outcome of candidate drugs/compounds besides saving precious time. CADD tools exploit structural and other information available regarding the target (enzyme/receptor) and the ligands to identify the compounds with the ability to treat diseases notably cancer, neurodegenerative disorders, malaria, Ebola, HIV-AIDS and many more. Computational approaches have led to the discovery of many drugs that have passed preclinical and clinical trials and become novel therapeutics in the treatment of a variety of diseases. Some notable examples of CADD derived novel drugs include dorzolamide, saquinavir, ritonavir, indinavir, captopril and tirofiban. CADD plays important role in predicting absorption, distribution, metabolism, excretion and toxicity (ADME/T) of candidate drugs. Overall, CADD represents an effective and much-needed strategy for designing therapeutically effective drugs to combat human diseases.

Systems Pharmacology in Small Molecular Drug Discovery.

Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.