Discovery of novel IDO1/TDO2 dual inhibitors: a consensus Virtual screening approach with molecular dynamics simulations, and binding free energy analysis.

The pursuit of effective cancer immunotherapy drugs remains challenging, with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) allowing cancer cells to evade immune attacks. While several IDO1 inhibitors have undergone clinical testing, only three dual IDO1/TDO2 inhibitors have reached human trials. Hence, this study focuses on identifying novel IDO1/TDO2 dual inhibitors through consensus structure-based virtual screening (SBVS). ZINC15 natural products library was refined based on molecular descriptors, and the selected compounds were docked to the holo form IDO1 and TDO2 using two different software programs and ranked according to their consensus docking scores. The top-scoring compounds underwent in silico evaluations for pharmacokinetics, toxicity, CYP3A4 affinity, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations. Five compounds (ZINC00000079405/10, ZINC00004028612/11, ZINC00013380497/12, ZINC00014613023/13, and ZINC00103579819/14) were identified as potential IDO1/TDO2 dual inhibitors due to their high consensus docking scores, key residue interactions with the enzymes, favorable pharmacokinetics, and avoidance of CYP3A4 binding. MD simulations of the top three hits with IDO1 indicated conformational changes and compactness, while MM-GBSA analysis revealed strong binding free energy for compounds 10 (ΔG: -20.13 kcal/mol) and 11 (ΔG: -16.22 kcal/mol). These virtual hits signify a promising initial step in identifying candidates as supplementary therapeutics to immune checkpoint inhibitors in cancer treatment. Their potential to deliver potent dual inhibition of IDO1/TDO2, along with safety and favorable pharmacokinetics, makes them compelling. Validation through in vitro and in vivo assays should be conducted to confirm their activity, selectivity, and preclinical potential as holo IDO1/TDO2 dual inhibitors.Communicated by Ramaswamy H. Sarma.

Identification of Potential Inhibitors of Three NDM Variants of Klebsiella Species from Natural Compounds: A Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Study.

BACKGROUND: Klebsiella species have emerged as well-known opportunistic pathogens causing nosocomial infections with ß-lactamase-mediated resistance as a prevalent antibiotic resistance mechanism. The discovery and emergence of metallo-ß-lactamases, mainly new- Delhi metallo-ß-lactamases (NDMs), have increased the threat and challenges in healthcare facilities. OBJECTIVE: A computational screening was conducted using 570 natural compounds from Dr. Duke's Phytochemical and Ethnobotanical data to discover promising inhibitors for NDM-6, NDM-9, and NDM-23 of the Klebsiella species. METHODS: Using homology modeling on the Raptor-X web server, the structures of the three NDM variants were predicted. The structures were validated using various computational tools and MD simulation for 50 ns. Lipinski - Vebers' Filter and ADMET Screening were used to screen 570 compounds, followed by docking in Biovia Discovery Studio 2019 using the CDOCKER module. GROMACS was used to simulate the compounds with the highest scores with the proteins for 50 ns. Using the MM-PBSA method and g_mmpbsa tool, binding free energies were estimated and per-residue decomposition analysis was conducted. RESULTS: The three structures predicted were found stable after the 50 ns MD Simulation run. The compounds Budmunchiamine-A and Rhamnocitrin were found to have the best binding energy towards NDM-6, NDM-9, and NDM-23, respectively. From the results of MD Simulation, MM-PBSA binding free energy calculations, and per-residue decomposition analysis, the Protein-ligand complex of NDM-6 with Budmunchiamine A and NDM-9 with Rhamnocitrin was relatively more stable than the complex of NDM-23 and Rhamnocitrin. CONCLUSION: The study suggests that Budmunchiamine-A and Rhamnocitrin are potential inhibitors of NDM-6 and NDM-9, respectively, and may pave a path for in-vivo and in-vitro studies in the future.

Ultra-high-resolution UAV-imaging and supervised deep learning for accurate detection of Alternaria solani in potato fields.

Alternaria solani is the second most devastating foliar pathogen of potato crops worldwide, causing premature defoliation of the plants. This disease is currently prevented through the regular application of detrimental crop protection products and is guided by early warnings based on weather predictions and visual observations by farmers. To reduce the use of crop protection products, without additional production losses, it would be beneficial to be able to automatically detect Alternaria solani in potato fields. In recent years, the potential of deep learning in precision agriculture is receiving increasing research attention. Convolutional Neural Networks (CNNs) are currently the state of the art, but also come with challenges, especially regarding in-field robustness. This stems from the fact that they are often trained on datasets that are limited in size or have been recorded in controlled environments, not necessarily representative of real-world settings. We collected a dataset consisting of ultra-high-resolution modified RGB UAV-imagery of both symptomatic and non-symptomatic potato crops in the field during various years and disease stages to cover the great variability in agricultural data. We developed a convolutional neural network to perform in-field detection of Alternaria, defined as a binary classification problem. Our model achieves a similar accuracy as several state-of-the-art models for disease detection, but has a much lower inference time, which enhances its practical applicability. By using training data of three consecutive growing seasons (2019, 2020 and 2021) and test data of an independent fourth year (2022), an F1 score of 0.93 is achieved. Furthermore, we evaluate how different properties of the dataset such as its size and class imbalance impact the obtained accuracy.

An Electronic Health Record-integrated Web Application Augments a QI-directed Morbidity & Mortality Conference and Improves Quality of Care.

BACKGROUND: In 2014, we developed a QI-directed Morbidity and Mortality (M&M) Conference, prioritizing discussion of individual and system failures, as well as development of action items to prevent failure recurrence. However, due to a reliance on individual electronic documents to store M&M data, our ability to assess trends in failures and action item implementation was hindered. To address this issue, in 2019, we created a secure electronic health record (EHR)-integrated web application (web app) to store M&M data. STUDY DESIGN: In this study, we assessed the impact of our web app on efficient review and tracking of M&M data, including system failure occurrence and closure of action items. Additionally, in 2021, it was discovered that a backlog of action items existed. To address this issue, we implemented a QI initiative to reduce the backlog, and used the web app to compare action item closure over time. RESULTS: Use of the web app dramatically improved review of M&M data. During the study period, there was a 67.0% reduction in the occurrence of the most common system failures. Additionally, our QI initiative resulted in a 97.7% reduction in the duration of time to complete a single action item and a 61.1% increase in the on-time closure rate for action items. CONCLUSIONS: Integration of a web app into a QI-directed M&M Conference enhanced our ability to track system level failures and action item closure over time. Using this web app, we demonstrated that our M&M Conference achieved its intended goal of improving the quality of patient care. LEVEL OF EVIDENCE: IV.

In silico investigation of cholesterol-lowering drugs to find potential inhibitors of dehydrosqualene synthase in Staphylococcus aureus.

Staphylococcus aureus is a lethal pathogen that can cause various bacterial infections. This study targets the CrtM enzyme of S. aureus, which is crucial for synthesizing golden carotenoid pigment: staphyloxanthin, which provides anti-oxidant activity to this bacterium for combating antimicrobial resistance inside the host cell. The present investigation quests for human SQS inhibitors against the CrtM enzyme by employing structure-based drug design approaches including induced fit docking (IFD), molecular dynamic (MD) simulations, and binding free energy calculations. Depending upon the docking scores, two compounds, lapaquistat acetate and squalestatin analog 20, were identified as the lead molecules exhibit higher affinity toward the CrtM enzyme. These docked complexes were further subjected to 100 ns MD simulation and several thermodynamics parameters were analyzed. Further, the binding free energies (ΔG) were calculated for each simulated protein-ligand complex to study the stability of molecular contacts using the MM-GBSA approach. Pre-ADMET analysis was conducted for systematic evaluation of physicochemical and medicinal chemistry properties of these compounds. The above study suggested that lapaquistat acetate and squalestatin analog 20 can be selected as potential lead candidates with promising binding affinity for the S. aureus CrtM enzyme. This study might provide insights into the discovery of potential drug candidates for S. aureus with a high therapeutic index. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03862-y.

The efficacy of Linum usitatissimum seeds to inhibit estrogen receptor as a natural therapy for PCOS: An in silico and in vitro analysis.

Polycystic ovarian syndrome (PCOS) is an endocrinological disorder aroused due to hormonal disturbances. It is characterized by anovulation due to an excess of androgen and estrogen hormones, thus leading to the formation of multiple cysts, imposing life-threatening conditions. This manuscript aimed to introduce a natural estrogen receptor (ESR) inhibitors that can provide protection against PCOS. The computational analysis of Linum usitatissimum seeds  compounds against ESR alpha receptor was performed, and the binding affinities of the ligand compounds and receptor proteins were scrutinized. Nine lignin compounds were docked, and the results were compared with that of reference estrogen receptor inhibitors, clomiphene, and tamoxifen. The binding affinity scores for pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol were -10.67, -10.66, -10.91, and -10.60 kcal mol-1 , respectively. These were comparable to the binding affinity score of reference compounds -11.406 kcal mol-1 for clomiphene and -10.666 kcal mol-1 for tamoxifen. Prime MM-GBSA studies showcased that Linum usitatissimum seeds compounds exhibit significant efficacy and efficiency towards receptor protein. Moreover, MD-simulation studies were performed and the results depict that the lignin compounds form stable complexes at 300 K throughout the simulation time. For further clarity, in-vitro experiments were carried out. The results exhibit the decline in cell proliferation in a concentration-dependent manner by extract 1 (ethyl acetate) EX1 and extract 2 (petroleum ether) EX2. Hence, providing evidence regarding the anti-estrogenic activity of the sample extracts. Collectively, these results showed that flax seed can reduce the levels of estrogen, which can induce ovulation and prevent cyst formation, and ultimately can provide protection against PCOS.

Solid-phase extraction with the functionalization of calcium-sensing receptors onto magnetic microspheres as an affinity probe can capture ligands selectively from herbal extract.

Magnetic solid phase extraction with the functionalization of protein onto micro- or nano-particles as a probe is favorable for the discovery of new drugs from complicated natural products. Herein, we aimed to develop a rapid method by immobilizing halogenated alkane dehalogenase (Halo)-tagged calcium-sensing receptor (CaSR) directly out of crude cell lysates onto the surface of magnetic microspheres (MM) with no need to purify protein. Thereby we achieved CaSR-functionalized MM for revealing adsorption characteristics of agonist neomycin and screening ligands from herbal medicine Radix Astragali (RA). About 43.87 mg CaSR could be immobilized per 1 g MM within 30 min, and the acquired CaSR-functionalized MM showed good stability and activity for 4 weeks. The maximum adsorption capacity of neomycin on CaSR-functionalized MM was determined as 4.70 × 10-4 ~ 3.96 × 10-4 mol/g within 277 ~ 310 K, and its adsorption isotherm characteristics described best by the Temkin model were further validated using isothermal titration calorimetry. It was inferred that CaSR's affinity for neomycin was driven by electrostatic forces in a spontaneous process when the system reached an equilibrium state. Moreover, the ligands from the RA extract were screened, three of which were assigned as astragaloside IV, ononin, and calycosin based on HPLC-MS. Our findings demonstrated that the functionalization of a receptor onto magnetic materials designed as an affinity probe has the capability to recognize its agonist and capture the ligands selectively from complex matrices like herbs.

The anticancer potential of chemical constituents of Moringa oleifera targeting CDK-2 inhibition in estrogen receptor positive breast cancer using in-silico and in vitro approches.

Most of the breast cancers are estrogen receptor-positive recurring with a steady rate of up to 20 years dysregulating the normal cell cycle. Dinaciclib is still in clinical trials and considered as a research drug against such cancers targeting CDK2.The major goal of this study was to identify the potential inhibitors of CDK-2 present in Moringa oleifera for treating hormonal receptor positive breast cancers. For this purpose, in silico techniques; molecular docking, MM-GBSA and molecular dynamics simulations were employed to screen Moringa oleifera compounds and their anticancer potential was determined against CDK-2 protein targets. Among 36 compounds of Moringa oleifera reported in literature, chlorogenic acid (1), quercetin (2), ellagic acid (3), niazirin (4), and kaempferol (5) showed good affinity with the target. The interaction of the compounds was visualized using PYMOL software. The profiles of absorption, distribution, metabolism, excretion (ADME) and toxicity were determined using SWISS and ProTox II webservers. The MTT assay was performed in-vitro using MCF-7 cancer cell lines to validate the anticancer potential of Moringa oleifera leaf extract.MTT assay results revealed no significant change in proliferation of Mcf-7 cells following 24 h treatment with fraction A (petroleum ether). However, significant antiproliferative effect was observed at 200 µg/mL dose of fraction B (ethyl acetate) and cell viability was reduced to 40%.In conclusion, the data suggested that all the compounds with highest negative docking score than the reference could be the potential candidates for cyclin dependent kinase-2 (CDK-2) inhibition while ellagic acid, chlorogenic acid and quercetin being the most stable and potent inhibitors to treat estrogen receptor positive breast cancer targeting CDK-2. Moreover, the data suggested that further investigation is required to determine the optimum dose for significant antiproliferative effects using in-vivo models to validate our findings of in-silico analysis.

Mutational analysis of flavonol synthase of M. pinnata towards enhancement of binding affinity: a computational approach.

Millettia pinnata is an important medicinal plant that has been used as a treatment of various diseases due to presence of wide range of pharmacological properties. The plant contains quercetin, kaempferol, karanjin, pongaglabrone, kanjone, kanugin, gammatin, pongaglabol, and other bioflavonoids. Kaempferol is a natural flavonol that shows many pharmacological properties including anti-inflammatory, antioxidant, anticancer, and antidiabetic activities etc. The enzyme flavonol synthase (FLS, EC 1.14.20.6) catalyses the conversion of dihydroflavonols to flavonols, i.e. biosynthesis of kaempferol from dihydrokaempferol. The current work examined the binding affinity-based approach to improve the enzyme catalytic activity using computational methods. Sequential site-directed mutagenesis was used to create four mutants with the goal to increase hydrogen bonds and further improving the ligand (dihydrokaempferol) binding efficiency. Simulations were done to monitor the stability of the mutants followed by molecular docking to confirm interactions with ligand. For structure validation, various dynamic analysis like RMSD, RMSF, ROG, SASA, H-bond, PCA, DCCM, and FEL were performed, which predicts the stability of wild-type (WT) proteins and mutants. The Mutant_2 and Mutant_3 showed maximum H-bonding and better stability than other mutants and WT that proved higher affinity suggesting improved catalysis. Mutant_2 and Mutant_3 exhibited binding affinities of -7.6 and -8.2 kcal/mol, respectively for the ligand. The outcome of present study will provide significant improvement in synthesis of kaempferol and other plant-based flavonoids.Communicated by Ramaswamy H. Sarma.

Modularized batch production of 12-inch transition metal dichalcogenides by local element supply.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) are regarded as pivotal semiconductor candidates for next-generation devices due to their atomic-scale thickness, high carrier mobility and ultrafast charge transfer. In analog to the traditional semiconductor industry, batch production of wafer-scale TMDs is the prerequisite to proceeding with their integrated circuits evolution. However, the production capacity of TMD wafers is typically constrained to a single and small piece per batch (mainly ranging from 2 to 4 inches), due to the stringent conditions required for effective mass transport of multiple precursors during growth. Here we developed a modularized growth strategy for batch production of wafer-scale TMDs, enabling the fabrication of 2-inch wafers (15 pieces per batch) up to a record-large size 12-inch wafers (3 pieces per batch). Each module, comprising a self-sufficient local precursor supply unit for robust individual TMD wafer growth, is vertically stacked with others to form an integrated array and thus a batch growth. Comprehensive characterization techniques, including optical spectroscopy, electron microscopy, and transport measurements unambiguously illustrate the high-crystallinity and the large-area uniformity of as-prepared monolayer films. Furthermore, these modularized units demonstrate versatility by enabling the conversion of as-produced wafer-scale MoS2 into various structures, such as Janus structures of MoSSe, alloy compounds of MoS2(1-x)Se2x, and in-plane heterostructures of MoS2-MoSe2. This methodology showcases high-quality and high-yield wafer output and potentially enables the seamless transition from lab-scale to industrial-scale 2D semiconductor complementary to silicon technology.

Terpenoid phytocompounds from mangrove plant Xylocarpus moluccensis as possible inhibitors against SARS-CoV-2: In silico strategy.

COVID-19 shook the world during the pandemic, where the climax it reached was vaccine manufacturing at an unfathomable pace. Alternative promising solutions to prevent infection from SARS-CoV-2 and its variants will remain crucial in the years to come. Due to its key role in viral replication, the major protease (Mpro) enzyme of SARS-CoV-2 can be an attractive therapeutic target. In the present work, natural terpenoids from mangrove medicinal plant Xylocarpus moluccensis (Lam.) M. Roem. were screened using computational methods for inhibition of Mpro protein. Out of sixty-seven terpenoids, Angolensic acid methyl ester, Moluccensin V, Thaixylomolin F, Godavarin J, and Xylomexicanolide A were shortlisted based on their docking scores and interaction affinities (- 13.502 to - 15.52 kcal/mol). The efficacy was validated by the 100 ns molecular dynamics study. Lead terpenoids were within the acceptable range of RMSD and RMSF with a mean value of 2.5 Å and 1.5 Å, respectively indicating that they bound tightly within Mpro and there was minimal fluctuation and stability of Mpro upon binding of these terpenoids. The utmost favorable binding strengths as calculated by MM-GBSA, were of Angolensic acid methyl ester and Moluccensin V with binding free energies (ΔGbind) of - 39.084, and - 43.160 kcal/mol, respectively. The terpenoids showed no violations in terms of Drug Likeliness and ADMET predictions. Overall, the findings indicate that Angolensic acid methyl ester and Moluccensin V are effective terpenoids having strong binding interaction with Mpro protein, which must be tested in vitro as an effective anti-SARS-CoV-2 drug.

In-silico and in-vitro assessments of some fabaceae, rhamnaceae, apocynaceae, and anacardiaceae species against Mycobacterium tuberculosis H37Rv and triple-negative breast cancer cells.

Medicinal plants play a huge role in the treatment of various diseases in the Limpopo province (South Africa). Traditionally, concoctions used for treating tuberculosis and cancer are sometimes prepared from plant parts naturally occurring in the region, these include (but not limited to) Schotia brachypetala, Rauvolfia caffra, Schinus molle, Ziziphus mucronate, and Senna petersiana. In this study, the aim was to evaluate the potential antimycobacterial activity of the five medicinal plants against Mycobacterium smegmatis mc2155, Mycobacterium aurum A + , and Mycobacterium tuberculosis H37Rv, and cytotoxic activity against MDA-MB 231 triple-negative breast cancer cells. Phytochemical constituents present in R. caffra and S. molle were tentatively identified by LC-QTOF-MS/MS as these extracts showed antimycobacterial and cytotoxic activity. A rigorous Virtual Screening Workflow (VSW) of the tentatively identified phytocompounds was then employed to identify potential inhibitor/s of M. tuberculosis pantothenate kinase (PanK). Molecular dynamics simulations and post-MM-GBSA free energy calculations were used to determine the potential mode of action and selectivity of selected phytocompounds. The results showed that plant crude extracts generally exhibited poor antimycobacterial activity, except for R. caffra and S. molle which exhibited average efficacy against M. tuberculosis H37Rv with minimum inhibitory concentrations between 0.25-0.125 mg/mL. Only one compound with a favourable ADME profile, namely, norajmaline was returned from the VSW. Norajmaline exhibited a docking score of -7.47 kcal/mol, while, pre-MM-GBSA calculation revealed binding free energy to be -37.64 kcal/mol. All plant extracts exhibited a 50% inhibitory concentration (IC50) of < 30 µg/mL against MDA-MB 231 cells. Flow cytometry analysis of treated MDA-MB 231 cells showed that the dichloromethane extracts from S. petersiana, Z. mucronate, and ethyl acetate extracts from R. caffra and S. molle induced higher levels of apoptosis than cisplatin. It was concluded that norajmaline could emerge as a potential antimycobacterial lead compound. Validation of the antimycobacterial activity of norajmaline will need to be performed in vitro and in vivo before chemical modifications to enhance potency and efficacy are done. S. petersiana, Z. mucronate, R.caffra and S. molle possess strong potential as key contributors in developing new and effective treatments for triple-negative breast cancer in light of the urgent requirement for innovative therapeutic solutions.

Antioxidant evaluation and computational prediction of prospective drug-like compounds from polyphenolic-rich extract of Hibiscus cannabinus L. seed as antidiabetic and neuroprotective targets: assessment through in vitro and in silico studies.

BACKGROUND: Reports have implicated diabetes mellitus (DM) and Alzheimer's disease (AD) as some of the global persistent health challenges with no lasting solutions, despite of significant inputs of modern-day pharmaceutical firms. This study therefore, aimed to appraise the in vitro antioxidant potential, enzymes inhibitory activities, and as well carry out in silico study on bioactive compounds from polyphenolic-rich extract of Hibiscus cannabinus seed (PEHc). METHODS: In vitro antioxidant assays were performed on PEHc using standard methods while the identification of phytoconstituents was carried out with high performance liquid chromatography (HPLC). For the in silico molecular docking using Schrodinger's Grid-based ligand docking with energetics software, seven target proteins were retrieved from the database ( https://www.rcsb.org/ ). RESULTS: HPLC technique identified twelve chemical compounds in PEHc, while antioxidant quantification revealed higher total phenolic contents (243.5 ± 0.71 mg GAE/g) than total flavonoid contents (54.06 ± 0.09 mg QE/g) with a significant (p < 0.05) inhibition of ABTS (IC50 = 218.30 ± 0.87 µg/ml) and 1, 1-diphenyl-2-picrylhydrazyl free radicals (IC50 = 227.79 ± 0.74 µg/ml). In a similar manner, the extract demonstrated a significant (p < 0.05) inhibitory activity against α-amylase (IC50 = 256.88 ± 6.15 µg/ml) and α-glucosidase (IC50 = 183.19 ± 0.23 µg/ml) as well as acetylcholinesterase (IC50 = 262.95 ± 1.47 µg/ml) and butyrylcholinesterase (IC50 = 189.97 ± 0.82 µg/ml), respectively. Furthermore, In silico study showed that hibiscetin (a lead) revealed a very strong binding affinity energies for DPP-4, (PDB ID: 1RWQ) and α-amylase (PDB ID: 1SMD), gamma-tocopherol ( for peptide-1 receptor; PDB ID: 3C59, AChE; PDB ID: 4EY7 and BChE; PDB ID: 7B04), cianidanol for α-glucosidase; PDB ID: 7KBJ and kaempferol for Poly [ADP-ribose] polymerase 1 (PARP-1); PDB ID: 6BHV, respectively. More so, ADMET scores revealed drug-like potentials of the lead compounds identified in PEHc. CONCLUSION: As a result, the findings of this study point to potential drug-able compounds in PEHc that could be useful for the management of DM and AD.

Repositioning Cannabinoids and Terpenes as Novel EGFR-TKIs Candidates for Targeted Therapy Against Cancer: A virtual screening model using CADD and biophysical simulations.

This study examines the potential of Cannabis sativa L. plants to be repurposed as therapeutic agents for cancer treatment through designing of hybrid Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). A set of 50 phytochemicals was taken from Cannabinoids and Terpenes and subjected for screening using Semi-flexible and Flexible Molecular Docking methods, MM-GBSA free binding energy computations, and pharmacokinetic/pharmacodynamic (ADME-Tox) predictions. Nine promising phytochemicals, Cannabidiolic acid (CBDA), Cannabidiol (CBD), Tetrahydrocannabivarin (THCV), Dronabinol (Δ-9-THC), Delta-8-Tetrahydrocannabinol (Δ-8-THC), Cannabicyclol (CBL), Delta9-tetrahydrocannabinolic acid (THCA), Beta-Caryophyllene (BCP), and Gamma-Elemene (γ-Ele) were identified as potential EGFR-TKIs natural product candidates for cancer therapy. To further validate these findings, a set of Molecular Dynamics simulations were conducted over a 200 ns trajectory. This hybrid early drug discovery screening strategy has the potential to yield a new generation of EGFR-TKIs based on natural cannabis products, suitable for cancer therapy. In addition, the application of this computational strategy in the virtual screening of both natural and synthetic chemical libraries could support the discovery of a wide range of lead drug agents to address numerous diseases.

(R)-(+)-Rosmarinic Acid as an Inhibitor of Herpes and Dengue Virus Replication: an In Silico Assessment.

Since ancient times, viruses such as dengue, herpes, Ebola, AIDS, influenza, chicken meat, and SARS have been roaming around causing great health burdens. Currently, the prescribed antiviral drugs have not cured the complications caused by viruses, whereas viral replication was not controlled by them. The treatments suggested are not only ineffectual, but also sometimes inefficient against viruses at all stages of the viral cycle as well. To fight against these contagious viruses, people rely heavily on medicinal plants to enhance their innate and adaptive immune systems. In this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap, and Glide XP, has each contributed significantly to the preparation of ligands and proteins. Ultimately, the research found that (R)-(+)-rosmarinic acid was found to have significant docking scores of - 10.847 for herpes virus, of - 10.033 for NS5, and - 7.259 for NS1. In addition, the Prediction of Activity Spectra for Substances (PASS) server indicates that rosmarinic acid possesses a diverse spectrum of enzymatic activities, as probability active (Pa) values start at > 0.751, whereas it has fewer adverse effects than the drugs prescribed for viruses. Accordingly, it was found the rate of acute toxicity values of (R)-(+)-rosmarinic acid at doses LD50 log10 (mmol/g) and LD50 (mg/g) in different routes of administration, such as intraperitoneal, intravenous, oral, and subcutaneous. Ultimately, the present study concluded that (R)-(+)-rosmarinic acid would expose significant antiviral effects in in vitro and in vivo experiments, and this research would be a valuable asset for the future, especially for those who wish to discover a drug molecule for a variety of viruses. Supplementary Information: The online version contains supplementary material available at 10.1007/s43450-023-00381-y.

Diosgenin and Monohydroxy Spirostanol from Prunus amygdalus var amara Seeds as Potential Suppressors of EGFR and HER2 Tyrosine Kinases: A Computational Approach.

Cancer continues to be leading cause of death globally, with nearly 7 million deaths per year. Despite significant progress in cancer research and treatment, there remain several challenges to overcome, including drug resistance, the presence of cancer stem cells, and high interstitial fluid pressure in tumors. To tackle these challenges, targeted therapy, specifically targeting HER2 (Human Epidermal Growth Factor Receptor 2) as well as EGFR (Epidermal Growth Factor Receptor), is considered a promising approach in cancer treatment. In recent years, phytocompounds have gained recognition as a potential source of chemopreventive and chemotherapeutic agents in tumor cancer treatment. Phytocompounds are compounds derived from medicinal plants that have the potential to treat and prevent cancer. This study aimed to investigate phytocompounds from Prunus amygdalus var amara seeds as inhibitors against EGFR and HER2 enzymes using in silico methods. In this study, fourteen phytocompounds were isolated from Prunus amygdalus var amara seeds and subjected to molecular docking studies to determine their ability to bind to EGFR and HER2 enzymes. The results showed that diosgenin and monohydroxy spirostanol exhibited binding energies comparable to those of the reference drugs, tak-285, and lapatinib. Furthermore, the drug-likeness and ADMET predictions, performed using the admetSAR 2.0 web-server tool, suggested that diosgenin and monohydroxy spirostanol have similar safety and ADMET properties as the reference drugs. To get deeper insight into the structural steadiness and flexibility of the complexes formed between these compounds and theEGFR and HER2 proteins, molecular dynamics simulations were performed for 100 ns. The results showed that the hit phytocompounds did not significantly affect the stability of the EGFR and HER2 proteins and were able to form stable interactions with the catalytic binding sites of the proteins. Additionally, the MM-PBSA analysis revealed that the binding free energy estimates for diosgenin and monohydroxy spirostanol is comparable to the reference drug, lapatinib. This study provides evidence that diosgenin and monohydroxy spirostanol may have the potential to act as dual suppressors of EGFR and HER2. Additional in vivo and in vitro research are needed to certify these results and assess their efficacy and safety as cancer therapy agents. The experimental data reported and these results are in agreement.

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors.

The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina's capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of -8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 µM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson-Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (-46.97 to -118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

Exploration of potent antiviral phytomedicines from Lauraceae family plants against SARS-CoV-2 RNA-dependent RNA polymerase.

RNA-dependent RNA polymerase, also known as RdRp, is a possible therapeutic target that could be used to suppress the proliferation of RNA viruses such as SARS-CoV-2. This protein has two major functional sites (a) catalytic and (b) substrate entry, which regulate the natural substrate entry and its corresponding interaction with the protein. In this study, a computational drug design pipeline was applied to investigate potential inhibitors against SARS-CoV-2 RdRp from Lauraceae plants, and five top hits were selected based on the docked score (< -7 kcal/mol). The docking study suggested that the Glochidioboside had a minimum binding score of -7.8 kcal/mol. This compound showed total five hydrogen bonds while two of them were with catalytic residues Asp618 and Asp760. However, another compound, Sitogluside showed a binding score of -7.3 kcal/mol with four hydrogen bonds targeting three functional residues (Arg555, Ser759, and Asp760). Later, 100 ns explicit solvent molecular dynamics (MD) simulation was performed to evaluate the stability of the protein-ligand docked system. These compounds translocated their positions from the catalytic site to the substrate entry site, as observed in the MD simulation trajectory. However, translocation did not affect the binding strength of these compounds, and they retained the strong binding affinity (ΔG < -11.5 kcal/mol), estimated using the MM/GBSA method. In general, the findings of this study indicated the potential therapeutic compounds that may be used targeting SARS-CoV-2 RdRp. However, these compounds still need to be validated by experimentation in order to determine their inhibitory function.Communicated by Ramaswamy H. Sarma.

Multitarget Potential of Phytochemicals from Traditional Medicinal Tree, Terminalia arjuna (Roxb. ex DC.) Wight & Arnot as Potential Medicaments for Cardiovascular Disease: An In-Silico Approach.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Terminalia arjuna (Roxb. ex DC.) Wight & Arnot of the Combretaceae family is one of the most frequently approved and utilized medicinal trees in the traditional medicinal system, which was used for the treatment of a variety of diseases, including cardiovascular disorders. The present study aims to identify phytochemicals from T. arjuna, that do not exhibit any toxicity and have significant cardioprotective activity using an in-silico technique. Four different cardiovascular proteins, namely human angiotensin receptor (PDB ID: 4YAY), P38 mitogen-activated protein kinase (MAPK, PDB ID: 4DLI), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase (PDB ID: 1HW9), and human C-reactive protein (PDB ID: 1B09), were used as target proteins to identify potential inhibitors using a virtual screening of the phytochemicals in T. arjuna revealed casuarinin as a potential inhibitor of all selected target proteins with strong binding energy. Furthermore, MD simulations for a 100 ns time scale also revealed that most of the key protein contacts of all target proteins were retained throughout the simulation trajectories. Binding free energy calculations using the MM-GBSA approach also support a strong inhibitory effect of casuarinin on target proteins. Casuarinin's effective binding to these proteins lays the groundwork for the development of broad-spectrum drugs as well as the understanding of the underlying mechanism against cardiovascular diseases through in vivo and clinical studies.

Phenolic compounds from Tradescantia pallida ameliorate diabetes by inhibiting enzymatic and non-enzymatic pathways.

Diabetes is a chronic metabolic disorder marked by postprandial hyperglycemia due to several etiologies including abnormal carbohydrate digestion and glycation of hemoglobin. The prolong use of synthetic drugs results in characteristic side effects which necessitates the discovery of safe and cost-effective substitutes. The aim of the current study is to isolate and evaluate the antidiabetic potential of the phenolic compounds from the leaves of Tradescantia pallida. Syringic acid, p-coumaric acid, morin and catechin (compounds 1-4) were isolated and characterized from Tradescantia pallida leaves using column chromatography and spectroscopic techniques. The in vitro antidiabetic potential of the phenolic compounds were assessed using α-amylase and non-enzymatic glycosylation of hemoglobin protein assays. A mechanistic insight of interactions between phenolic compounds and human α-amylase and hemoglobin protein were scrutinized by employing molecular docking method. Prime Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations were carried out to find the binding energies of the ligand-protein complexes. Morin and catechin were further analyzed to find the dynamic and thermodynamic constraints of the complexes under specific biological conditions using molecular dynamic simulation trajectories. The stability and flexibility of the complexes were justified by fluctuation of α-carbon chain, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and type of interactions involved which authenticated the in vitro inhibitory potential of morin and catechin against enzymatic and non-enzymatic pathways. The current study could be fruitful in rational designing of safe antidiabetic drugs of natural origin.Communicated by Ramaswamy H. Sarma.