Evaluation of In Vitro Antimicrobial, Cytotoxic, Thrombolytic, and Antiarthritic Property of Different Parts of Bari Orchid.

Many different herbal extracts have historically been utilized to treat microbe-induced infections, injuries, cancer, thrombosis, and arthritis. The purpose of this study was to determine the antibacterial, cytotoxic, in vitro thrombolytic, and in vitro antiarthritic properties of ethanolic extracts of stem and seed of Bari orchid 1 (BO) plant. This orchid plant was developed by the Bangladesh Agriculture Research Institute (BARI) in Gazipur. Fourteen microbes were employed in the antimicrobial investigation, and samples of orchids were compared to ciprofloxacin as a reference. The BO/seed extract was found to possess more antibacterial activity. The lethality test of brine shrimps was used to assess the LC50 values. The BO/stem extract exhibited a higher cytotoxicity potential, in comparison to the BO/seed extract. Two concentrations (1000 and 100 ppm) and two incubation times (24 hours and 1.5 hours) were used to assess the thrombolytic activity of the extracts. Regarding the thrombolytic effect, the BO/stem extract has demonstrated greater promise. Furthermore, the herbal extract's antiarthritic activity was investigated at four different concentrations, and the results were evaluated in comparison with those of diclofenac sodium. When comparing BO/stem extract to other extracts, the greatest values for protein denaturation were obtained.

Identification of new potent NLRP3 inhibitors by multi-level in-silico approaches.

Nod-like receptor protein 3 (NLRP-3), is an intracellular sensor that is involved in inflammasome activation, and the aberrant expression of NLRP3 is responsible for diabetes mellitus, its complications, and many other inflammatory diseases. NLRP3 is considered a promising drug target for novel drug design. Here, a pharmacophore model was generated from the most potent inhibitor, and its validation was performed by the Gunner-Henry scoring method. The validated pharmacophore was used to screen selected compounds databases. As a result, 646 compounds were mapped on the pharmacophore model. After applying Lipinski's rule of five, 391 hits were obtained. All the hits were docked into the binding pocket of target protein. Based on docking scores and interactions with binding site residues, six compounds were selected potential hits. To check the stability of these compounds, 100 ns molecular dynamic (MD) simulations were performed. The RMSD, RMSF, DCCM and hydrogen bond analysis showed that all the six compounds formed stable complex with NLRP3. The binding free energy with the MM-PBSA approach suggested that electrostatic force, and van der Waals interactions, played a significant role in the binding pattern of these compounds. Thus, the outcomes of the current study could provide insights into the identification of new potential NLRP3 inflammasome inhibitors against diabetes and its related disorders.

Flavonoids as potential KRAS inhibitors: DFT, molecular docking, molecular dynamics simulation and ADMET analyses.

KRAS mutations linked with cancer. Flavonoids were docked against KRAS G12C and G12D receptors. Abyssinone III, alpha naphthoflavone, beta naphthoflavone, abyssinone I, abyssinone II and beta naphthoflavone, genistin, daidzin showed good docking scores against KRAS G12C and G12D receptors, respectively. The MD simulation data revealed that Rg, RMSD, RMSF, and SASA values were within acceptable limits. Alpha and beta naphthoflavone showed good binding energies with KRAS G12C and G12D receptors. DFT and MEP analysis highlighted the nucleophilic and electrophilic zones of best-docked flavonoids. A novel avenue for the control of KRAS G12C and G12D mutations is made possible by flavonoids.

In the present study, we computationally established the role of flavonoids as KRAS G12C and G12D inhibitors.Initially we selected 93 flavonoids and docked against 8AFB (KRAS G12C) and 7RT1 (KRAS G12D) using Sotorasib and MRTX 1133 as standards.A 100 ns MD simulation revealed that the radius of gyration, RMSD, RMSF, and SASA values were within acceptable limits and that there were a greater number of donors and acceptors for hydrogen bonds.In addition to the KRAS G12C 8AFB receptor, the maximum binding energy was shown by alpha Naphthoflavone (−26.471 kJ/mol), and for the KRAS G12D 7RT1 receptor, the maximum binding energy was shown by beta Naphthoflavone (−15.433 kJ/mol).FMO and MEP analysis data highlighted the best-docked flavonoids' potential areas for nucleophilic and electrophilic attacks.ADMET properties have been calculated and provide safe use and low toxicity for both aquatic and non-aquatic species.

Prospective virtual screening combined with bio-molecular simulation enabled identification of new inhibitors for the KRAS drug target.

Lung cancer is a disease with a high mortality rate and it is the number one cause of cancer death globally. Approximately 12-14% of non-small cell lung cancers are caused by mutations in KRASG12C. The KRASG12C is one of the most prevalent mutants in lung cancer patients. KRAS was first considered undruggable. The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. Drug development is a challenging, expensive, and time-consuming process. Recently, machine-learning-based virtual screening are used for the development of new drugs. In this study, we performed machine-learning-based virtual screening followed by molecular docking, all atoms molecular dynamics simulation, and binding energy calculations for the identifications of new inhibitors against the KRASG12C mutant. In this study, four machine learning models including, random forest, k-nearest neighbors, Gaussian naïve Bayes, and support vector machine were used. By using an external dataset and 5-fold cross-validation, the developed models were validated. Among all the models the performance of the random forest (RF) model was best on the train/test dataset and external dataset. The random forest model was further used for the virtual screening of the ZINC15 database, in-house database, Pakistani phytochemicals, and South African Natural Products database. A total of 100 ns MD simulation was performed for the four best docking score complexes as well as the standard compound in complex with KRASG12C. Furthermore, the top four hits revealed greater stability and greater binding affinities for KRASG12C compared to the standard drug. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at ( https://github.com/Amar-Ajmal/Datasets-for-KRAS ).

In-silico and in-vitro evaluation of antifungal bioactive compounds from Streptomyces sp. strain 130 against Aspergillus flavus.

Streptomyces spp. are considered excellent reservoirs of natural bioactive compounds. The study evaluated the bioactive potential of secondary metabolites from Streptomyces sp. strain 130 through PKS-I and NRPS gene-clusters screening. GC-MS analysis was done for metabolic profiling of bioactive compounds from strain 130 in the next set of experiments. Identified antifungal compounds underwent ADMET analyses to screen their toxicity. All compounds' molecular docking was done with the structural gene products of the aflatoxin biosynthetic pathway of Aspergillus flavus. MD simulations were utilized to evaluate the stability of protein-ligand complexes under physiological conditions. Based on the in-silico studies, compound 2,4-di-tert butyl-phenol (DTBP) was selected for in-vitro studies against Aspergillus flavus. Simultaneously, bioactive compounds were extracted from strain 130 in two different solvents (ethyl-acetate and methanol) and used for similar assays. The MIC value of DTBP was found to be 314 µg/mL, whereas in ethyl-acetate extract and methanol-extract, it was 250 and 350 µg/mL, respectively. A mycelium growth assay was done to analyze the effect of compounds/extracts on the mycelium formation of Aspergillus flavus. In agar diffusion assay, zone of inhibitions in DTBP, ethyl-acetate extract, and methanol extract were observed with diameters of 11.3, 13.3, and 7.6 mm, respectively. In the growth curve assay, treated samples have delayed the growth of fungi, which signified that the compounds have a fungistatic nature. Spot assay has determined the fungal sensitivity to a sub-minimum inhibitory concentration of antifungal compounds. The study's results suggested that DTBP can be exploited for antifungal-drug development.Communicated by Ramaswamy H. Sarma.

A hierarchical approach towards identification of novel inhibitors against L, D-transpeptidase YcbB as an anti-bacterial therapeutic target.

The bacterial cell wall, being a vital component for cell viability, is regarded as a promising drug target. The L, D-Transpeptidase YcbB enzyme has been implicated for a significant role in cell wall polymers cross linking during typhoid toxin release, ß-lactam resistance and outer membrane defect rescue. These observations have been recorded in different bacterial pathogens such as Salmonella Typhimurium, Citrobacter rodentium, and Salmonella typhi. In this work, we have shown structure based virtual screening of diverse natural and synthetic drug libraries against the enzyme and revealed three compounds as LAS_32135590, LAS_34036730 and LAS-51380924. These compounds showed highly stable energies and the findings are very competitive with the control molecule ((1RG or (4 R,5S)-3-({(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl}sulfanyl)-5-[(1S,2R)-1-formyl-2-hydroxypropyl]-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid or ertapenem)) used. Compared to control (which has binding energy score of -11.63 kcal/mol), the compounds showed better binding energy. The binding energy score of LAS_32135590, LAS_34036730 and LAS-51380924 is -12.63 kcal/mol, -12.22 kcal/mol and -12.10 kcal/mol, respectively. Further, the docked snapshot of the lead compounds and control were investigated for stability under time dependent dynamics environment. All the three leads complex and control system showed significant equilibrium (mean RMSD < 3 Å) both in term of intermolecular docked conformation and binding interactions network. Further validation on the complex's stability was acquired from the end-state MMPB/GBSA analysis that observed greater contribution from van der Waals forces and electrostatic energy while less contribution was noticed from solvation part. The compounds were also showed good drug-likeness and are non-toxic and non-mutagenic. In short, the compounds can be used in experimental testing's and might be subjected to structure modification to get better results.Communicated by Ramaswamy H. Sarma.

Intelligent Millimeter-Wave System for Human Activity Monitoring for Telemedicine.

Telemedicine has the potential to improve access and delivery of healthcare to diverse and aging populations. Recent advances in technology allow for remote monitoring of physiological measures such as heart rate, oxygen saturation, blood glucose, and blood pressure. However, the ability to accurately detect falls and monitor physical activity remotely without invading privacy or remembering to wear a costly device remains an ongoing concern. Our proposed system utilizes a millimeter-wave (mmwave) radar sensor (IWR6843ISK-ODS) connected to an NVIDIA Jetson Nano board for continuous monitoring of human activity. We developed a PointNet neural network for real-time human activity monitoring that can provide activity data reports, tracking maps, and fall alerts. Using radar helps to safeguard patients' privacy by abstaining from recording camera images. We evaluated our system for real-time operation and achieved an inference accuracy of 99.5% when recognizing five types of activities: standing, walking, sitting, lying, and falling. Our system would facilitate the ability to detect falls and monitor physical activity in home and institutional settings to improve telemedicine by providing objective data for more timely and targeted interventions. This work demonstrates the potential of artificial intelligence algorithms and mmwave sensors for HAR.

Identification of novel inhibitors against VP40 protein of Marburg virus by integrating molecular modeling and dynamics approaches.

Marburg virus (MV) is a highly etiological agent of haemorrhagic fever in humans and has spread across the world. Its outbreaks caused a 23-90% human death rate. However, there are currently no authorized preventive or curative measures yet. VP40 is the MV matrix protein, which builds protein shell underneath the viral envelope and confers hallmark filamentous. VP40 alone is able to induce assembly and budding of filamentous virus-like particles (VLPs), which resemble authentic virions. As a result, this research is credited with clarifying the function of VP40 and leading to the discovery of new therapeutic targets effective in combating MV disease (MVD). Virtual screening, molecular docking and molecular dynamics (MD) simulation were used to find the putative active chemicals based on a 3D pharmacophore model of the protein's active site cavity. Initially, andrographidine-C, a potent inhibitor was selected for the development of the pharmacophore model. Later, a library of 30,000 compounds along with the andrographidine-C was docked against VP40 protein. Three best hits including avanafil, diuvaretin and macrourone were subjected to further MD simulation analysis, as these compounds had better binding affinities as compared to andrographidine-C. Furthermore, throughout the 100 ns simulations, the back bone of VP40 protein in presence of avanafil, diuvaretin and macrourone remained stable which was further validated by MM-PBSA analysis. Additionally, all of these compounds depict maximum drug-like properties. The predicted drugs based on the ligand, avanafil, diuvaretin and macrourone could be exploited and developed as an alternative or complementary therapy for the treatment of MVD.Communicated by Ramaswamy H. Sarma.

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection.

The Marburg virus (MBV), a deadly pathogen, poses a serious threat to world health due to the lack of effective treatments, calling for an immediate search for targeted and efficient treatments. In this study, we focused on compounds originating from marine fungi in order to identify possible inhibitory compounds against the Marburg virus (MBV) VP35-RNA binding domain (VP35-RBD) using a computational approach. We started with a virtual screening procedure using the Lipinski filter as a guide. Based on their docking scores, 42 potential candidates were found. Four of these compounds-CMNPD17596, CMNPD22144, CMNPD25994, and CMNPD17598-as well as myricetin, the control compound, were chosen for re-docking analysis. Re-docking revealed that these particular compounds had a higher affinity for MBV VP35-RBD in comparison to the control. Analyzing the chemical interactions revealed unique binding properties for every compound, identified by a range of Pi-cation interactions and hydrogen bond types. We were able to learn more about the dynamic behaviors and stability of the protein-ligand complexes through a 200-nanosecond molecular dynamics simulation, as demonstrated by the compounds' consistent RMSD and RMSF values. The multidimensional nature of the data was clarified by the application of principal component analysis, which suggested stable conformations in the complexes with little modification. Further insight into the energy profiles and stability states of these complexes was also obtained by an examination of the free energy landscape. Our findings underscore the effectiveness of computational strategies in identifying and analyzing potential inhibitors for MBV VP35-RBD, offering promising paths for further experimental investigations and possible therapeutic development against the MBV.

Network pharmacology and molecular dynamic simulation integrated strategy for the screening of active components and mechanisms of phytochemicals from Datura innoxia on Alzheimer and cognitive decline.

Alzheimer's disease (AD) ranks as the most prevalent neurodegenerative disorder with dementia and it accounts for more than 70% of all cases. Despite extensive reporting on the experimental investigation of Datura innoxia (DI) and its phytochemical components in the treatment of AD, the urgent need for elucidation of the principle of multi-mechanism and multi-level treatment of AD remains. In this research, molecular docking and network pharmacology were used to evaluate active compounds and molecular targets of DI for the treatment of AD. The phytochemical compounds of DI were obtained from the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) as well as the Traditional Chinese Medicine System Pharmacology (TCMSP) databases. The screening includes the 28 most abundant components of DI and the Swiss Target Prediction database was used to predict targets of these compounds. The GeneCards database was used to collect AD-related genes. Both DI and AD targets were imported into a Venn diagram, and the 28 overlapped genes were identified as potential DI anti-AD targets. The results showed that Dinoxin B, Meteloidine, Scopoline, and Tropic acid had no effect on AD-related genes. Furthermore, the GO enrichment analysis indicates that DI influences molecular functions and biological processes such as learning or memory and modulation of chemical synaptic transmission as well as the membrane raft and membrane microdomain. The KEGG pathway analysis revealed that the key pathways implicated in DI's anti-AD actions include serotonergic synapse, IL-17 signaling pathway, and AGE-RAGE signaling pathway in diabetic complications. Based on the STRING and Cytoscape network-analysis platforms, the top ten anti-AD core targets include APP, CASP3, IL6, BACE1, IL1B, ACE, PSEN1, GAPDH, GSK3B and ACHE. The molecular docking and molecular dynamic simulation of the top two molecules against the top three target proteins confirmed the strong binding affinity and stability at the docked site. Overall, our findings pave the path for further research into the development and optimization of potential anti-AD agents from DI.Communicated by Ramaswamy H. Sarma.

DFT insights into LaFeO3 with Mn substitution: A promising path to energy-efficient magneto-optical applications.

In recent years, the demand for electronic materials has significantly increased, driven by industrial needs and the pursuit of cost-efficient alternatives. This comprehensive study investigates the effects of Mn substitution on LaFeO3 through the implementation of the GGA approach in density functional theory. The research findings demonstrate remarkable consistency with the experimental outcomes reported in the existing literature pertaining to the studied compounds. However, this study unveils novel insights into the mechanical and optical characteristics of the doped structures, which have not been previously reported. The structural stability is rigorously examined through multiple stability criteria, encompassing structural optimization, tests of elastic stability, and enthalpy of formation calculations. Furthermore, the electronic and optical properties of the compounds exhibit exceptional improvements in conductivity and reflectivity as a result of the doping process. The band structure analysis reveals the presence of a Moss-Burstein shift. Investigation of the magnetic properties indicates an increase in the magnetic moment value due to the Fe-Mn degeneracy resulting from increased Mn content. Mechanical analysis of the elastic moduli B, G, and Y demonstrates an enhanced strength and metal-like conductivity, attributed to the induced anharmonicity. Moreover, the internal strain factor suggests a higher degree of bond flexibility, implying potential applications of these compounds in flexible electronics.

Identification of novel STAT3 inhibitors for liver fibrosis, using pharmacophore-based virtual screening, molecular docking, and biomolecular dynamics simulations.

The signal transducer and activator of transcription 3 (STAT3) plays a fundamental role in the growth and regulation of cellular life. Activation and over-expression of STAT3 have been implicated in many cancers including solid blood tumors and other diseases such as liver fibrosis and rheumatoid arthritis. Therefore, STAT3 inhibitors are be coming a growing and interesting area of pharmacological research. Consequently, the aim of this study is to design novel inhibitors of STAT3-SH3 computationally for the reduction of liver fibrosis. Herein, we performed Pharmacophore-based virtual screening of databases including more than 19,481 commercially available compounds and in-house compounds. The hits obtained from virtual screening were further docked with the STAT3 receptor. The hits were further ranked on the basis of docking score and binding interaction with the active site of STAT3. ADMET properties of the screened compounds were calculated and filtered based on drug-likeness criteria. Finally, the top five drug-like hit compounds were selected and subjected to molecular dynamic simulation. The stability of each drug-like hit in complex with STAT3 was determined by computing their RMSD, RMSF, Rg, and DCCM analyses. Among all the compounds Sa32 revealed a good docking score, interactions, and stability during the entire simulation procedure. As compared to the Reference compound, the drug-like hit compound Sa32 showed good docking scores, interaction, stability, and binding energy. Therefore, we identified Sa32 as the best small molecule potent inhibitor for STAT3 that will be helpful in the future for the treatment of liver fibrosis.

Network pharmacology based virtual screening of Flavonoids from Dodonea angustifolia and the molecular mechanism against inflammation.

Inflammation is a nonspecific immune response against injury caused by a harmful agent that strives to restore tissue function and homeostasis. Dodonaea angustifolia L.f. (Sapindaceae) is a medium-sized shrub used to treat a variety of diseases in traditional medicine. In the current study, integrated network-pharmacology and molecular docking approaches were used to identify the active constituents, their possible targets, signaling pathways, and anti-inflammatory effects of flavonoids from D.angustifolia. D. angustifolia active ingredients were acquired from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), and Traditional Chinese Medicine System Pharmacology (TCMSP) databases. The screening included the ten most prevalent D. angustifolia components, and the SwissTargetPrediction database was utilized to anticipate the targets of these compounds. Anti-inflammatory genes were found using the GeneCards database. The 175 overlapping genes were discovered as prospective D. angustifolia anti-inflammatory targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the overlapped targets were closely related to the major pathogenic processes linked to inflammation, such as response to organonitrogen compound, protein kinase activity, phosphotransferase activity, pI3k-Akt signaling pathway, metabolic pathways, and chemical carcinogenesis. Compound-target-pathway, and protein-protein interaction networks revealed 6-Methoxykaempferol and 5-Hydroxy-7,8 dimethoxyflavone as key compounds, and AKT1, VEGFA, and EGFR as key targets. Furthermore, molecular docking followed by molecular dynamic (MD) simulation of D. angustifolia active ingredients with core proteins fully complemented the binding affinity of these compounds and indicated stable complexes at the docked site. These findings reveal D. angustifolia 's multi-target, multi-compound, and multi-pathway strategies against inflammation. Our study paved the way for further research into the mechanism for developing D. angustifolia -based natural products as alternative therapies for inflammation.

Investigating the role of Sterol C24-Methyl transferase mutation on drug resistance in leishmaniasis and identifying potential inhibitors.

Leishmaniasis is a fatal disease caused by the leishmania parasite. For the survival of the leishmania parasite, Sterol C24-Methyl Transferase (SMT) is essential which is an enzyme of the ergosterol pathway. SMT protein mutation is responsible for Amphotericin-B drug resistance in Leishmania, which is the main treatment for visceral leishmaniasis. Amphotericin-B resistance is caused by three mutated residues V131I, V321I and F72C. The underlying mechanisms and structural changes in SMT enzymes responsible for resistance due to mutation are still not well understood. In the current study, the potential mechanism of resistance due to these mutations and the structure variation of wild and mutant SMT proteins were investigated through molecular dynamics simulations and molecular docking analysis. The results showed that AmB established strong bonding interaction with wild SMT as compare to mutants SMT. The binding energy calculation showed that binding energy of AmB with mutants SMT increases as compare to the wild SMT. Further structural based virtual screening was carried out to design potential inhibitors for the mutant SMT. On the basis of structural-based virtual screening four inhibitors (SANC01057, SANC00882, SANC00414, SANC01047) were computationally identified as potential mutant SMT (F72C) inhibitors. This work provides valuable information for improved management of drug resistant Leishmaniasis.Communicated by Ramaswamy H. Sarma.

Design, Synthesis, ADME, and Anticancer Studies of Newer N-Aryl-5-(3,4,5-Trifluorophenyl)-1,3,4-Oxadiazol-2-Amines: An Insight into Experimental and Theoretical Investigations.

In continuance of our investigation into the anticancer activity of oxadiazoles, we report here the preparation of 10 new 1,3,4-oxadiazole analogues using the scaffold hopping technique. We have prepared the oxadiazoles having a common pharmacophoric structure (oxadiazole linked aryl nucleus) as seen in the reported anticancer agents IMC-038525 (tubulin inhibitor), IMC-094332 (tubulin inhibitor), and FATB (isosteric replacement of the S of thiadiazole with the O of oxadiazole). All of the oxadiazole analogues were predicted for their absorption, distribution, metabolism, and excretion (ADME) profiles and toxicity studies. All of the compounds were found to follow Lipinski's rule of 5 with a safe toxicity profile (Class IV compound) against immunotoxicity, mutagenicity, and toxicity. All of the compounds were synthesized and characterized using spectral data, followed by their anticancer activity tested in a single-dose assay at 10 µM as reported by the National Cancer Institute (NCI US) Protocol against nearly 59 cancer cell lines obtained from nine panels, including non-small-cell lung, ovarian, breast, central nervous system (CNS), colon, leukemia, prostate, and cancer melanoma. N-(2,4-Dimethylphenyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-amine (6h) displayed significant anticancer activity against SNB-19, OVCAR-8, and NCI-H40 with percent growth inhibitions (PGIs) of 86.61, 85.26, and 75.99 and moderate anticancer activity against HOP-92, SNB-75, ACHN, NCI/ADR-RES, 786-O, A549/ATCC, HCT-116, MDA-MB-231, and SF-295 with PGIs of 67.55, 65.46, 59.09, 59.02, 57.88, 56.88, 56.53, 56.4, and 51.88, respectively. The compound 6h also registered better anticancer activity than Imatinib against CNS, ovarian, renal, breast, prostate, and melanoma cancers with average PGIs of 56.18, 40.41, 36.36, 27.61, 22.61, and 10.33, respectively. Molecular docking against tubulin, one of the appealing cancer targets, demonstrated an efficient binding within the binding site of combretastatin A4. The ligand 6h (docking score = -8.144 kcal/mol) interacted π-cationically with the residue Lys352 (with the oxadiazole ring). Furthermore, molecular dynamic (MD) simulation studies in complex with the tubulin-combretastatin A4 protein and ligand 6h were performed to examine the dynamic stability and conformational behavior.

Synthesis and Anticancer Evaluation of 4-Chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol Analogues: An Insight into Experimental and Theoretical Studies.

We report herein the synthesis, docking studies and biological evaluation of a series of new 4-chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol analogues (6a-h). The new compounds were designed based on the oxadiazole-linked aryl core of tubulin inhibitors of IMC-038525 and IMC-094332, prepared in five steps and further characterized via spectral analyses. The anticancer activity of the compounds was assessed against several cancer cell lines belonging to nine different panels as per National Cancer Institute (NCI US) protocol. 4-Chloro-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)phenol (6h) demonstrated significant anticancer activity against SNB-19 (PGI = 65.12), NCI-H460 (PGI = 55.61), and SNB-75 (PGI = 54.68) at 10 µM. The compounds were subjected to molecular docking studies against the active site of the tubulin-combretastatin A4 complex (PDB ID: 5LYJ); they displayed efficient binding and ligand 4h (with docking score = -8.030 kcal/mol) lay within the hydrophobic cavity surrounded by important residues Leu252, Ala250, Leu248, Leu242, Cys241, Val238, Ile318, Ala317, and Ala316. Furthermore, the antibacterial activity of some of the compounds was found to be promising. 4-Chloro-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)amino)phenol (6c) displayed the most promising antibacterial activity against both Gram-negative as well as Gram-positive bacteria with MICs of 8 µg/mL and a zone of inhibition ranging from 17.0 ± 0.40 to 17.0 ± 0.15 mm at 200 µg/mL; however, the standard drug ciprofloxacin exhibited antibacterial activity with MIC values of 4 µg/mL.

Egyptian mandarin peel oil's anti-scabies potential via downregulation-of-inflammatory/immune-cross-talk: GC-MS and PPI network studies.

The current study investigated the scabicidal potential of Egyptian mandarin peel oil (Citrus reticulata Blanco, F. Rutaceae) against sarcoptic mange-in-rabbits. Analysis of the oil's GC-MS identified a total of 20 compounds, accounting for 98.91% of all compounds found. Mandarin peel oil topical application improved all signs of infection, causing a scabicidal effect three days later, whereas in vitro application caused complete mite mortality one day later. In comparison to ivermectin, histopathological analysis showed that the epidermis' inflammatory-infiltration/hyperkeratosis-had disappeared. In addition to TIMP-1, the results of the mRNA gene expression analysis showed upregulation of I-CAM-1-and-KGF and downregulation of ILs-1, 6, 10, VEGF, MMP-9, and MCP-1. The scabies network was constructed and subjected to a comprehensive bioinformatic evaluation. TNF-, IL-1B, and IL-6, the top three hub protein-coding genes, have been identified as key therapeutic targets for scabies. From molecular docking data, compounds 15 and 16 acquired sufficient affinity towards the three screened proteins, particularly both possessing higher affinity towards the IL-6 receptor. Interestingly, it achieved a higher binding energy score than the ligand of the docked protein rather than displaying proper binding interactions like those of the ligand. Meanwhile, geraniol (15) showed the highest affinity towards the GST protein, suggesting its contribution to the acaricidal effect of the extract. The subsequent, MD simulations revealed that geraniol can achieve stable binding inside the binding site of both GST and IL-6. Our findings collectively revealed the scabicidal ability of mandarin peel extract for the first time, paving the way for an efficient, economical, and environmentally friendly herbal alternative for treating rabbits with Sarcoptes mange.

Vitis vinifera leaf extract liposomal Carbopol gel preparation's potential wound healing and antibacterial benefits: in vivo, phytochemical, and computational investigation.

Vitis vinifera Egyptian edible leaf extract loaded on a soybean lecithin, cholesterol, and Carbopol gel preparation (VVL-liposomal gel) was prepared to maximize the in vivo wound healing and anti-MRSA activities for the crude extract, using an excision wound model and focusing on TLR-2, MCP-1, CXCL-1, CXCL-2, IL-6 and IL-1ß, and MRSA (wound infection model, and peritonitis infection model). VVL-liposomal gel was stable with significant drug entrapment efficiency reaching 88% ± 3, zeta potential value ranging from -50 to -63, and a size range of 50-200 µm nm in diameter. The in vivo evaluation proved the ability of VVL-liposomal gel to gradually release the drugs in a sustained manner with greater complete wound healing effect and tissue repair after 7 days of administration, with a significant decrease in bacterial count compared with the crude extract. Phytochemical investigation of the crude extract of the leaves yielded fourteen compounds: two new stilbenes (1, 2), along with twelve known ones (3-14). Furthermore, a computational study was conducted to identify the genes and possible pathways responsible for the anti-MRSA activity of the isolated compounds, and inverse docking was used to identify the most likely molecular targets that could mediate the extract's antibacterial activity. Gyr-B was discovered to be the best target for compounds 1 and 2. Hence, VVL-liposomal gel can be used as a novel anti-dermatophytic agent with potent wound healing and anti-MRSA capacity, paving the way for future clinical research.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Bioinformatics and network pharmacology-based study to elucidate the multi-target pharmacological mechanism of the indigenous plants of Medina valley in treating HCV-related hepatocellular carcinoma.

The incidence of Hepatocellular Carcinoma (HCC) in Saudi Arabia is not surprising given the relatively high prevalence of hepatitis C virus (HCV) infection. Hepatitis C is also common in Saudi Arabia with a prevalence rate of 1% to 3% of the population, which further increases the risk of HCC. The incidence of HCC has been increasing in recent years, with HCV-related HCC accounting for a significant proportion of cases. Traditional medicine has long been a part of Saudi Arabian culture, and many medicinal plants have been used for centuries to treat various ailments, including cancer. Following that, this study combines network pharmacology with bioinformatics approaches to potentially revolutionize HCV-related HCC treatment by identifying effective phytochemicals of indigenous plants of Medina valley. Eight indigenous plants including Rumex vesicarius, Withania somnifera, Rhazya stricta, Heliotropium arbainense, Asphodelus fistulosus, Pulicaria incise, Commicarpus grandiflorus, and Senna alexandrina, were selected for the initial screening of potential drug-like compounds. At first, the information related to active compounds of eight indigenous plants was retrieved from public databases and through literature review which was later combined with differentially expressed genes (DEGs) obtained through microarray datasets. Later, a compound-target genes-disease network was constructed which uncovered that kaempferol, rhazimol, beta-sitosterol, 12-Hydroxy-3-keto-bisnor-4-cholenic acid, 5-O-caffeoylquinic acid, 24-Methyldesmosterol, stigmasterone, fucosterol, and withanolide_J decisively contributed to the cell growth and proliferation by affecting ALB and PTGS2 proteins. Moreover, the molecular docking and Molecular Dynamic (MD) simulation of 20 ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. But the findings were not validated in actual patients, so further investigation is needed to confirm the potential use of selected medicinal plants towards HCV-related HC.