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The apple is an important part of the human diet and is one of the most popular fruits in Morocco, with varieties that are now suitable for human consumption. This study aims to clarify several aspects of apples, such as their physical and chemical compositions and nutrient profiles. Total polyphenols, flavonoids, tannins, and anthocyanins were determined using spectrophotometer and organic acid compounds were identified by high-performance liquid chromatography-ultraviolet. The results show a significant difference between the several varieties under study in terms of their physico-chemical and phyto-chemical characteristics. In general, the studied apples are juiciness, with a percentage ranging from 60 to 71%. The pH values demonstrate how acidic the apples are. The Brix parameter denotes values greater than 13°Brix. Total polyphenols and condensed tannins (1154.65 ± 13.54 µg EAG/g and 514.09 ± 32.40 µg EAT/g, respectively) are more present in the Ahjjani variety than they are in other varieties. This demonstrates their good nutritional quality while not being consumable. However, the Story variety has a predominance of flavonoids (75.074 ± 2.309 µg QE/g) and flavones (45.074 ± 2.09 µg QE/g). The detection of organic acids has shown that the acid succinic is the most abundant in all the varieties of studied apple fruits. These results allow us to infer that non-consumable varieties are also important dietary sources of bioactive molecules, notably for polyphenols. The fact that these kinds can be used to produce other byproducts is therefore highly intriguing.

Given the critical role of survivin (BIRC5) in tumor cell regulation, developing novel inhibitors represents a promising approach for cancer therapy. This study details the design of innovative survivin inhibitors based on the hydroxyquinoline scaffold of our previously reported lead compound, MX-106. Our study identified nine compounds whose inhibitory activity is expected to be superior to that of the most active molecule in the series. These compounds demonstrated potent suppression of MDA-MB-435 breast cancer cell proliferation in vitro and exhibited enhanced metabolic stability compared to the series' most active member. To evaluate these derivatives as potential survivin inhibitors, we employed a multi-faceted approach combining 2D-QSAR methods, molecular docking, molecular dynamics, and ADMET property assessment. Our molecular modeling studies led to the design of nine novel compounds (Pred1-Pred9) predicted to exhibit potent survivin inhibitory activity based on MLR models. To assess their suitability as drug candidates, we recommend a thorough evaluation of their ADMET properties. These compounds hold promise as innovative anticancer agents targeting survivin, similar to the established MX-106., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

GluN2B-induced activation of NMDA receptors plays a key function in central nervous system (CNS) disorders, including Parkinson, Alzheimer, and stroke, as it is strongly involved in excitotoxicity, which makes selective NMDA receptor antagonists one of the potential therapeutic agents for the treatment of neurodegenerative diseases, especially stroke. The present study aims to examine a structural family of thirty brain-penetrating GluN2B N-methyl-D-aspartate (NMDA) receptor antagonists, using virtual computer-assisted drug design (CADD) to discover highly candidate drugs for ischemic strokes. Initially, the physicochemical and ADMET pharmacokinetic properties confirmed that C13 and C22 compounds were predicted as non-toxic inhibitors of CYP2D6 and CYP3A4 cytochromes, with human intestinal absorption (HIA) exceeding 90%, and designed to be as efficient central nervous system (CNS) agents due to the highest probability to cross the blood-brain barrier (BBB). Compared to ifenprodil, a co-crystallized ligand complexed with the transport protein encoded as 3QEL.pdb, we have noticed that C13 and C22 chemical compounds were defined by good ADME-Toxicity profiles, meeting Lipinski, Veber, Egan, Ghose, and Muegge rules. The molecular docking results indicated that C22 and C13 ligands react specifically with the amino acid residues of the NMDA receptor subunit GluN1 and GluN2B. These intermolecular interactions produced between the candidate drugs and the targeted protein in the B chain remain stable over 200 nanoseconds of molecular dynamics simulation time. In conclusion, C22 and C13 ligands are highly recommended as anti-stroke therapeutic drugs due to their safety and molecular stability towards NMDA receptors.Communicated by Ramaswamy H. Sarma.

Based on a structural family of thirty-two NR2B-selective N-Methyl-D-Aspartate receptor (NMDAR) antagonists, two phenylpiperazine derivatives labeled C37 and C39 were conceived thanks to molecular modeling techniques, as novel NMDAR inhibitors exhibiting the highest analgesic activities (of pIC 50 order) against neuropathic pain, with excellent ADME-toxicity profiles, and good levels of molecular stability towards the targeted protein of NMDA receptor. Initially, the quantitative structure-activity relationships (QSARs) models were developed using multiple linear regression (MLR), partial least square regression (PLSR), multiple non-linear regression (MNLR), and artificial neural network (ANN) techniques, revealing that analgesic activity was strongly correlated with dipole moment, octanol/water partition coefficient, Oxygen mass percentage, electronegativity, and energy of the lowest unoccupied molecular orbital, whose the correlation coefficients of generated models were: 0.860, 0.758, 0.885 and 0.977, respectively. The predictive capacity of each model was evaluated by an external validation with correlation coefficients of 0.703, 0.851, 0.778, and 0.981 respectively, followed by a cross-validation technique with the leave-one-out procedure (CVLOO) with Q 2 cv of 0.785, more than Y-randomization test, and applicability domain (AD), in addition to Fisher's and Student's statistical tests. Thereafter, ten novel molecules were designed based on MLR QSAR model, then predicted with their ADME-Toxicity profiles and subsequently examined for their similarity to the drug candidates. Finally, two of the most active compounds (C37 and C39) were chosen for molecular docking and molecular dynamics (MD) investigations during 100 ns of MD simulation time in complex with the targeted protein of NMDA receptor (5EWJ.pdb)., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Opuntia ficus-indica (L.) Mill is frequently observed in the Moroccan traditional medicinal system, where these approaches are employed to mitigate the onset of diabetes and the subsequent complications it may entail., Aim of the Study: The aim of this research was to examine the effectiveness of Opuntia ficus-indica seed oil in preventing diabetic complications. Specifically, the study assessed its ability to counteract glycation at various stages, protected red blood cells from the harmful effects of glycated albumin, and inhibited pancreatic lipase digestive enzymes to understand its potential antihyperglycemic properties. Additionally, the study aimed to identify the chemical components responsible for these effects, evaluate antioxidant and anti-inflammatory properties, and conduct computational investigations such as molecular docking., Materials and Methods: The assessement of Opuntia ficus-indica seed oil antiglycation properties involved co-incubating the extract oil with a bovine serum albumin-glucose glycation model. The study investigated various stages of glycation, incorporating fructosamine (inceptive stage), protein carbonyls (intermediate stage), and AGEs (late stage). Additionally, measurement of β-amyloid aggregation of albumin was performed using Congo red, which is specific to amyloid structures. Additionally, the evaluation of oil's safeguarding effect on erythrocytes against toxicity induced by glycated albumin included the measurement of erythrocyte hemolysis, lipid peroxidation, reduced glutathione. The fatty acid of Opuntia ficus-indica seed oil were analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). The in vitro evaluation of antihyperglycemic activity involved the use of pancreatic lipase enzyme, while the assessement of antioxidant capability was carried out through the utilization of the ABTS and FRAP methods. The in vitro assessement of the denaturation of albumin activity was also conducted. In conjunction with the experimental outcomes, computational investigations were undertaken, specifically employing ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. Furthermore, molecular docking was utilized to predict antioxidant and antiglycation mechanisms based on protein targets., Results: In vitro glycation assays, Opuntia ficus-indica seed oil displayed targeted inhibitory effects at multiple distinct stages. Within erythrocytes, in addition to mitigating hemolysis and lipid peroxidation induced by glycated albumin. GC-MS investigation revealed a richness of fatty acids and the most abundant compounds are Linoleic acid (36.59%), Palmitic acid (20.84%) and Oleic acid (19.33%) respectively. The findings of antioxidant ability showed a remarkable activity on FRAP and ABTS radicals. This oil showed a pronounced inhibitory impact (p < 0.001) on pancreatic lipase enzyme. It also exerted a notibale inhibition of albumin denaturation, in vitro., Conclusion: The identified results were supported by the abundant compounds of fatty acids unveiled through GC-MS analysis, along with the computational investigation and molecular docking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Coriandrum sativum L. essential oil (CS-EO) is being evaluated in vitro for its antioxidant and antimicrobial properties, and its volatile compounds are to be identified as part of this exploratory study. Methods: The processes underlying the in vitro biological properties were explained using in silico simulations, including drug-likeness prediction, molecular docking, and pharmacokinetics (absorption, distribution, metabolism, excretion, and toxicity-ADMET). Chemical screening of CS-EO was conducted using gas chromatography-mass spectrometry (GC-MS). Five in vitro complementary techniques were used to assess the antioxidant activity of CS-EO: reducing power (RP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonate) (ABTS) radical scavenging activity, β-Carotene bleaching test (BCBT), and phosphomolybdenum assay (TAC). Results: According to GC-MS analysis, linalool (59.04%), γ-Terpinene (13.02%), and α-Pinene (6.83%) are the main constituents of CS-EO. Based on the in vitro antioxidant assay results, CS-EO has been found to have a superior antioxidant profile. Its estimated scavenging rates for ABTS + are 0.51 ± 0.04 mg/mL, BCBT is 9.02 ± 0.01 mg/mL, and CS-EO is 1.52 ± 0.14 mg/mL. C. sativum demonstrated 6.13 ± 0.00 μg/mL for reducing power and 213.44 ± 0.45 mg AAE/mL for total antioxidant activity. The in vitro antimicrobial activity of CS-EO was assessed against five strains, including two gram-positive bacteria, two gram-negative bacteria, and one fungal strain ( Candida albicans ). Significant antibacterial and antifungal activities against all strains were found using the disc-diffusion assay, with zones of inhibition larger than 15 mm. The microdilution test highlighted the lowest MIC and MBC values with gram-positive bacteria, ranging from 0.0612 to 0.125% v/v for MIC and 0.125% v/v for MBC. The fungal strain's MFC was 1.0% v/v and its MIC was measured at 0.5%. Based on the MBC/MIC and MFC/MIC ratios, CS-EO exhibits bactericidal and fungicidal activity. The ADMET study indicates that the primary CS-EO compounds are good candidates for the development of pharmaceutical drugs due to their favorable pharmacokinetic properties. Conclusion: These results point to a potential application of this plant as a natural remedy and offer empirical backing for its traditional uses. It is a promising environmentally friendly preservative that can be used extensively in the food and agricultural industries to prevent aflatoxin contamination and fungal growth in stored goods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nouioura, El fadili, El Hachlafi, Maache, Mssillou, A. Abuelizz, Lafdil, Er-rahmani, Lyoussi and Derwich.)

Novel isoxazole-triazole conjugates have been efficiently synthesized using 3-formylchromone as starting material according to a multi-step synthetic approach. The structures of the target conjugates and intermediate products were characterized by standard spectroscopic techniques ( 1 H NMR and 13 C NMR) and confirmed by mass spectrometry (MS). The all-synthesized compounds were screened for their antibacterial activity against three ATCC reference strains, namely Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC BAA-44, and Escherichia coli ATCC 25922 as well as one strain isolated from the hospital environment Pseudomonas aeruginosa . The findings indicate that conjugate 7b exhibits a stronger antibacterial response against the tested Escherichia coli ATCC 25922 and Pseudomonas aeruginosa pathogenic strains compared to the standard antibiotics. Furthermore, hybrid compound 7b proved to have a bactericidal action on the Escherichia coli ATCC 25922 strain, as evidenced by the results of the MBC determination. Moreover, the ADMET pharmacokinetic characteristics revealed a favorable profile for the examined compound, as well as a good level of oral bioavailability. Molecular docking and molecular dynamics simulations were performed to explore the inhibition mechanism and binding energies of conjugate 7b with the proteins of Escherichia coli and Pseudomonas aeruginosa bacterial strains. The in silico results corroborated the data observed in the in vitro evaluation for compound 7b .

This study focused on developing new inhibitors for the MCF-7 cell line to contribute to our understanding of breast cancer biology and various experimental techniques. 3D QSAR modeling was used to design new tetrahydrobenzo[4, 5]thieno[2, 3-d]pyrimidine derivatives with good characteristics. Two robust 3D-QSAR models were developed, and their predictive capacities were confirmed through high correlations [CoMFA (Q 2 = 0.62, R 2 = 0.90) and CoMSIA (Q 2 = 0.71, R 2 = 0.88)] via external validations (R 2 ext = 0.90 and R 2 ext = 0.91, respectively). These successful evaluations confirm the potential of the models to provide reliable predictions. Six candidate inhibitors were discovered, and two new inhibitors were developed in silico using computational methods. The ADME-Tox properties and pharmacokinetic characteristics of the new derivatives were evaluated carefully. The interactions between the new tetrahydrobenzo[4, 5]thieno[2, 3-d]pyrimidine derivatives and the protein ERα (PDB code: 4XO6) were highlighted by molecular docking. Additionally, MM/GBSA calculations and molecular dynamics simulations provided interesting information on the binding stabilities between the complexes. The pharmaceutical characteristics, interactions with protein, and stabilities of the inhibitors were examined using various methods, including molecular docking and molecular dynamics simulations over 100 ns, binding free energy calculations, and ADME-Tox predictions, and compared with the FDA-approved drug capivasertib. The findings indicate that the inhibitors exhibit significant binding affinities, robust stabilities, and desirable pharmaceutical characteristics. These newly developed compounds, which act as inhibitors to mitigate breast cancer, therefore possess considerable potential as prospective drug candidates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zarougui, Er-Rajy, Faris, Imtara, El fadili, Qurtam, Nasr, Al-Zharani and Elhallaoui.)

This study investigated the effects of storage conditions on the quality of chilled ram semen stored at 4°C for 48 h, comparing aerobic and anaerobic conditions. Ejaculates from INRA180 rams were collected and stored under both conditions, with assessments at 0-, 24-, and 48-h intervals. Various sperm parameters were examined, including motility, velocity, viability, morphology, membrane integrity, and lipid peroxidation. Results showed that storage duration significantly impacted sperm quality, leading to a gradual decline from 0 to 24 h and 24 to 48 h. Notably, after the initial 24 h, progressive motility (PM) and membrane integrity (MI) demonstrated distinct responses to storage conditions. Anaerobic storage consistently improved PM and MI values compared to aerobic storage between 24 and 48 h. Anaerobic conditions also enhanced viability and reduced abnormality at the 48-h mark. Total motility remained stable throughout storage. Velocity parameters (VCL: curvilinear velocity; VSL: straight velocity and VAP: velocity average path) exhibited differences between the 24- and 48-h intervals, with anaerobic storage resulting in higher VAP and VSL values. Moreover, lipid peroxidation exhibited a progressive increase from 0 to 24 h and 24 to 48 h, independent of storage conditions. Remarkably, anaerobic storage consistently yielded lower lipid peroxidation levels compared to aerobic storage, regardless of storage duration. In conclusion, this study highlights that the anaerobic storage proved advantageous for chilled ram semen quality, particularly after the initial 24 h., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

This exploratory study aims to identify the volatile compounds in PC-Eo ( Petroselinum crispum L. essential oil) and evaluate its antioxidant and antimicrobial properties in vitro . Molecular docking, drug-likeness prediction, and pharmacokinetics (absorption, distribution, metabolism, excretion, and toxicity-ADMET) were among the in silico simulations that were used to explain the biological properties observed in vitro . For PC-Eo's chemical screening, gas chromatography-mass spectrophotometry (GC-MS) was employed. The antioxidant activity of PC-Eo was evaluated using five in vitro complementary techniques, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radical scavenging activity, β-Carotene bleaching test (BCBT), reducing power (RP), and phosphomolybdenum assay (TAC). GC-MS analysis revealed that the primary components of PC-Eo are apiol (49.05 %), Myristicin (21.01 %), and 1-allyl-2,3,4,5-tetramethoxybenzene (13.14 %). The results of the in vitro antioxidant assays indicate that PC-Eo exhibits a superior antioxidant profile. The in vitro antimicrobial activity of PC-Eo was assessed against five strains, including 2 g-positive bacteria, 2 g-negative bacteria, and one fungal strain ( Candida albicans ). The disc-diffusion assay revealed significant antibacterial and antifungal activities against all strains, with zones of inhibition exceeding 15 mm. The microdilution test highlighted the lowest MIC and MBC values with gram-positive bacteria, ranging from 0.25 to 0.5 % v/v for MIC and 0.5-1.0 % v/v for MBC. For the fungal strain, MIC was recorded at 1.25 % and MFC at 2.5 % v/v. PC-Eo demonstrates bactericidal and fungicidal activity based on the MBC/MIC and MFC/MIC ratios. According to the ADMET study, the primary PC-Eo compounds have advantageous pharmacokinetic characteristics. These findings provide empirical support for the traditional uses of this plant and indicate its possible use as a natural remedy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsHatem A. Abuelizz reports financial support was provided by 10.13039/501100002383King Saud University, Riyadh, Saudi Arabia. Hatem A. Abuelizz reports a relationship with 10.13039/501100002383King Saud University, Riyadh, Saudi Arabia. that includes: board membership and funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Although giant fennel is recognized as a "superfood" rich in phytochemicals with antioxidant activity, research into the antibacterial properties of its fruits has been relatively limited, compared to studies involving the root and aerial parts of the plant. In this study, seven solvents-acetone, methanol, ethanol, ethyl acetate, chloroform, water, and hexane-were used to extract the chemical constituents of the fruit of giant fennel (Ferula communis), a species of flowering plant in the carrot family Apiaceae. Specific attributes of these extracts were investigated using in silico simulations and in vitro bioassays. High-performance liquid chromatography equipped with a diode-array detector (HPLC-DAD) identified 15 compounds in giant fennel extract, with p-coumaric acid, 3-hydroxybenzoic acid, sinapic acid, and syringic acid being dominant. Among the solvents tested, ethanol demonstrated superior antioxidant activity and phenolic and flavonoid contents. F. communis extracts showed advanced inhibition of gram-negative pathogens (Escherichia coli and Proteus mirabilis) and variable antifungal activity against tested strains. Molecular docking simulations assessed the antioxidative, antibacterial, and antifungal properties of F. communis, facilitating innovative therapeutic development through predicted compound-protein interactions. In conclusion, the results validate the ethnomedicinal use and potential of F. communis. This highlights its significance in natural product research and ethnopharmacology., (© 2024. The Author(s).)

Morocco is known for its high plant biodiversity, but many plants are poorly valorized. For this reason, this study aims to valorize the methanolic and aqueous extracts of Melitotus albus leaves by studying their antioxidant activity and toxicity. The extracts' antioxidant activity is assessed using the FRAP, DPPH, CAT, and ABTS methods. The chemical composition was determined using LC-MS analysis and evaluated using in silico studies. The results revealed that the total polyphenol content of the aqueous extract, 259.26 ± 7.79 (mg GAE/g), is higher than that of the methanolic extract, 131.41 ± 12.64 (mg GAE/g). The antioxidant activity by the methods of DPPH, ABTS, and phosphor molybdenum of aqueous extracts (0.087 ± 0.015, 0.014 ± 0.001 and 6.157 ± 1.050 mg eq vit C/g, respectively) is greater than that of methanolic extracts (0.107 ± 0.02, 0.167 ± 0.03, and 0.453 ± 0.014 mg eq vit C/g, respectively). The reducing power of iron (FRAP) shows that the methanolic extract has a greater reducing power than that of the aqueous extract with a low IC50 (0.011 ± 0.003 and 0.199 ± 0.016 mg/mL, respectively). The study of acute and subacute toxicity shows that the administration of the aqueous extract of M. albus at different doses increases the body weight of rats without modifying their general behavior. The M. albus extract had a 99.99% total phenolic content, as determined by LC-MS, consisting of 12 different components. The primary constituents of the extract are chlorogenic acid (43.68%), catechin/epicatechin (24.82%), quercetin-3- O -glucuronic acid (9.91%), naringin (7.64%), and p -hydroxybenzoic/salicylic acid (2.95%). The in-silico study showed that these compounds can passively permeate through the blood and have a beneficial effect on various organs of the body. Based on these results, M. albus can be used as a medicinal plant in phytotherapy, cosmetics, or as a dietary supplement. The bioactive compounds of these plants will require a lot of further effort in terms of isolation and characterization., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Dysphania ambrosioides L. (Chenopodiaceae) is a Moroccan medicinal plant known locally as "M'Khinza." It is widely used in traditional medicine to treat numerous ailments, such as diabetes, digestive disorders, fever, fertility problems, immune disorders, hypertension, bronchitis, respiratory conditions, pharyngitis, cough, and flu. As part of this review, comprehensive preclinical investigations, including in vitro, in vivo, and in silico studies, were conducted to better understand the mechanisms of action of D. ambrosioides. Additionally, the phytochemical profile of the plant was examined, highlighting the presence of certain bioactive secondary metabolites. The information was gathered from electronic data sources such as Web of Science, PubMed, Science Direct, Scopus, Springer Link, and Google Scholars. Numerous studies have mentioned the pharmacological properties of D. ambrosioides, including its antioxidant, anti-inflammatory, antiparasitic, antiviral, antibacterial, and antifungal activities. Furthermore, research has also suggested its potential as an anticancer, antidiabetic, and vasorelaxant agent. Phytochemical characterization of D. ambrosioides has revealed the presence of over 96 major bioactive compounds, including terpenoids, polyphenols, flavonoids, alkaloids, and fatty acids. As for the toxicity of this plant, it is dose-dependent. Furthermore, more in-depth pharmacological studies are needed to establish the mechanisms of action of this plant more accurately before considering clinical trials. In conclusion, this review highlights the traditional use of D. ambrosioides in Moroccan medicine and emphasizes its potential pharmacological properties. However, to fully harness its therapeutic potential, further research, both in terms of chemistry and pharmacology, is necessary. These future studies could help identify new active compounds and provide a better understanding of the mechanisms of action of this plant, thus opening new prospects for its pharmaceutical application., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Modeling the structural properties of novel morpholine-bearing 1, 5-diaryl-diazole derivatives as potent COX-2 inhibitor, two proposed models based on CoMFA and CoMSIA were evaluated by external and internal validation methods. Partial least squares analysis produced statistically significant models with Q 2 values of 0.668 and 0.652 for CoMFA and CoMSIA, respectively, and also a significant non-validated correlation coefficient R² with values of 0.882 and 0.878 for CoMFA and CoMSIA, respectively. Both models met the requirements of Golbraikh and Tropsha, which means that both models are consistent with all validation techniques. Analysis of the CoMFA and CoMSIA contribution maps and molecular docking revealed that the R1 substituent has a very significant effect on their biological activity. The most active molecules were evaluated for their thermodynamic stability by performing MD simulations for 100 ns; it was revealed that the designed macromolecular ligand complex with 3LN1 protein exhibits a high degree of structural and conformational stability. Based on these results, we predicted newly designed compounds, which have acceptable oral bioavailability properties and would have high synthetic accessibility., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In recent years, there has been a focus on developing and discovering novel Bruton's tyrosine kinase (BTK) inhibitors, as they offer an effective treatment strategy for B-cell malignancies. BTK plays a crucial role in B cell receptor (BCR)-mediated activation and proliferation by regulating downstream factors such as the NF-κB and MAP kinase pathways. To address this challenge and propose potential therapeutic options for B-cell lymphomas, researchers conducted 2D-QSAR and ADMET studies on pyrrolopyrimidine derivatives that act as inhibitors of the BCR site in cytochrome b . These studies aim to improve and identify new compounds that could serve as more potent potential BTK inhibitors, which would lead to the identification of new drug candidates in this field. In our study, we used 2D-QSAR (multiple linear regression, multiple nonlinear regression, and artificial neural networks), molecular docking, molecular dynamics, and ADMET properties to investigate the potential of 35 pyrrolopyrimidine derivatives as BTK inhibitors. A molecular docking study and molecular dynamics simulations of molecule 13 over 10 ns revealed that it establishes multiple hydrogen bonds with several residues and exhibits frequent stability throughout the simulation period. Based on the results obtained by molecular modeling, we proposed six new compounds (Pred1, Pred2, Pred3, Pred4, Pred5, and Pred6) with highly significant predicted activity by MLR models. A study based on the in silico evaluation of the predicted ADMET properties of the new candidate molecules is strongly recommended to classify these molecules as promising candidates for new anticancer agents specifically designed to target Bruton's tyrosine kinase (BTK) inhibition., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

A structural class of forty glycine transporter type 1 (GlyT1) inhibitors, was examined using molecular modeling techniques. The quantitative structure-activity relationships (QSAR) technology confirmed that human GlyT1 activity is strongly and significantly affected by constitutional, geometrical, physicochemical and topological descriptors. ADME-Tox in-silico pharmacokinetics revealed that L28 and L30 ligands were predicted as non-toxic inhibitors with a good ADME profile and the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicated that the predicted inhibitors block GlyT1, reacting specifically with Phe319, Phe325, Tyr123, Tyr 124, Arg52, Asp475, Ala117, Ala479, Ile116 and Ile483 amino acids of the dopamine transporter (DAT) membrane protein. These results were qualified and strengthened using molecular dynamics (MD) study, which affirmed that the established intermolecular interactions for (L28, L30-DAT protein) complexes remain perfectly stable along 50 ns of MD simulation time. Therefore, they could be strongly recommended as therapeutics in medicine to improve memory performance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.

Tropomyosin receptor kinase (TRK) enzymes are responsible for different types of tumors caused by neurotrophic tyrosine receptor kinase gene fusion and have been identified as an effective target for anticancer therapy. The study of the mechanism between polo-like kinase (PLKs) and pyrazol inhibitors was performed using 3D-QSAR modeling, molecular docking, and MD simulations in order to design high-activity inhibitors. The HQSAR ( Q 2  = 0.793, R 2  = 0.917, R 2 ext  = 0.961), CoMFA ( Q 2  = 0.582, R 2  = 0.722, R 2 ext  = 0.951), CoMSIA/SE ( Q 2  = 0.603, R 2  = 0.801, R 2 ext  = 0.849), and Topomer CoMFA ( Q 2  = 0.726, R 2  = 0.992, R 2 ext  = 0.717) showed good reliability and predictability. All models have been successfully tested by external validation, so all five established models are reliable. The analysis of the different contour maps of different models gives structural information to improve the inhibitory function. Molecular docking results show that the amino acids Met 592, GLU 590, LEU 657, VAL 524, and PHE 589 are the active sites of the tropomyosin receptor TRKs. The results obtained by MD showed that compound 19i could form a more stable complex protein (PDB id: 5KVT). Based on these results, we developed new compounds and their expected inhibitory activities. The results of physicochemical and ADME-Tox properties showed that the four proposed molecules are orally bioavailable, and they are not toxic in the Ames test. Thus, these results would provide modeling information that could help experimental researchers find TRK type I inhibitors more efficiently.Communicated by Ramaswamy H. Sarma.

Forty-four bicyclo ((aryl) methyl) benzamides, acting as glycine transporter type 1 (GlyT1) inhibitors, are developed using molecular modeling techniques. QSAR models generated by multiple linear and non-linear regressions affirm that the biological inhibitory activity against the schizophrenia disease is strongly and significantly correlated with physicochemical, geometrical and topological descriptors, in particular: Hydrogen bond donor, polarizability, surface tension, stretch and torsion energies and topological diameter. According to in silico ADMET properties, the most active ligands (L6, L9, L30, L31 and L37) are the molecules having the highest probability of penetrating the central nervous system (CNS), but the molecule 32 has the highest probability of being absorbed by the gastrointestinal tract. Molecular docking results indicate that Tyr124, Phe43, Phe325, Asp46, Phe319 and Val120 amino acids are the active sites of the dopamine transporter (DAT) membrane protein, in which the most active ligands can inhibit the glycine transporter type 1 (GlyT1). The results of molecular dynamics (MD) simulation revealed that all five inhibitors remained stable in the active sites of the DAT protein during 100 ns, demonstrating their promising role as candidate drugs for the treatment of schizophrenia.

The present study was undertaken to assess the effect of seasons on scrotal circumference, semen characteristics, seminal plasma composition, and sperm motility during liquid storage of INRA180 rams. The semen was collected from five mature INRA180 rams (2-3 years of age) during one year (from April 2014 to March 2015). Scrotal circumferences, semen characteristics, some biochemical parameters of seminal plasma were evaluated. Immediately after collection and evaluation, the semen was pooled and extended in skim milk (SM) at 15°C to reach 0.8×109 spermatozoa/ml. Thereafter, samples were evaluated at different storage times (0, 8, and 24h). The results showed that scrotal circumference, semen quality and the concentration of total protein in seminal plasma were relatively constant during the year (P>0.05). However, total lipid and cholesterol concentrations increased significantly (P<0.001) in winter and summer. The result showed also that progressive motility was higher in winter and summer after 24h of storage (P<0.01). In contrast, no difference was recorded regarding total motility (P>0.05). To conclude, the INRA180 rams have the ability to produce semen with high quality all over the year. The only parameters showing seasonal variations are cholesterol, total lipid, and progressive motility., (Copyright © 2017 Elsevier B.V. All rights reserved.)