QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy.

Breast cancer remains a leading cause of cancer-related deaths among women globally, necessitating the development of more effective therapeutic agents with minimal side effects. This study explores novel 1,2,4-triazine-3(2H)-one derivatives as potential inhibitors of Tubulin, a pivotal protein in cancer cell division, highlighting a targeted approach in cancer therapy. Using an integrated computational approach, we combined quantitative structure-activity relationship (QSAR) modeling, ADMET profiling, molecular docking, and molecular dynamics simulations to evaluate and predict the efficacy and stability of these compounds. Our QSAR models, developed through rigorous statistical analysis, revealed that descriptors such as absolute electronegativity and water solubility significantly influence inhibitory activity, achieving a predictive accuracy (R2) of 0.849. Molecular docking studies identified compounds with high binding affinities, particularly Pred28, which exhibited the best docking score of - 9.6 kcal/mol. Molecular dynamics simulations conducted over 100 ns provided further insights into the stability of these interactions. Pred28 demonstrated notable stability, with the lowest root mean square deviation (RMSD) of 0.29 nm and root mean square fluctuation (RMSF) values indicative of a tightly bound conformation to Tubulin. The novelty of this work lies in its methodological rigor and the integration of multiple advanced computational techniques to pinpoint compounds with promising therapeutic potential. Our findings advance the current understanding of Tubulin inhibitors and open avenues for the synthesis and experimental validation of these compounds, aiming to offer new solutions for breast cancer treatment.

Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives.

More people are being diagnosed with resistant breast cancer, increasing the urgency of developing new effective treatments. Several lines of evidence suggest that blocking the kinase activity of VEGFR-2 reduces angiogenesis and slows tumor growth. In this study, we developed novel VEGFR-2 inhibitors based on the triazolopyrazine template by using comparative molecular field analysis (CoMFA) and molecular similarity indices (CoMSIA) models for 3D-QSAR analysis of 23 triazolopyrazine-based compounds against breast cancer cell lines (MCF -7). Both CoMFA (Q2 = 0.575; R 2 = 0.936, Rpred 2 = 0.956) and CoMSIA/SE (Q2 = 0.575; R 2 = 0.936, Rpred 2 = 0.847) results demonstrate the robustness and stability of the constructed model. Six novel compounds with potent inhibitory activity were carefully designed, and screening of ADMET properties revealed their good oral bioavailability and ability to diffuse through various biological barriers. When compared with the most active molecule in the data set and with Foretinib (breast cancer drug), molecular docking revealed that the six designed compounds had strengthened affinity (-8.9 to -10 kcal/mol) to VEGFR-2. Molecular Dynamics Simulations and MMPBSA calculations were applied to the selected compound T01 with the highest predicted inhibitory activity, confirming its stability in the active pocket of VEGFR-2 over 100 ns. The present results provided the basis for the chemical synthesis of new compounds with improved inhibitory properties against the breast cancer cell line (MCF -7).

Unleashing Nature's potential: a computational approach to discovering novel VEGFR-2 inhibitors from African natural compound using virtual screening, ADMET analysis, molecular dynamics, and MMPBSA calculations.

One of the characteristic features of cancer is angiogenesis, the process by which new, aberrant blood vessels are formed from pre-existing blood vessels. The process of angiogenesis begins when VEGF binds to its receptor, the VEGF receptor (VEGFR). The formation of new blood vessels provides nutrients that can promote the growth of cancer cells. When it comes to new blood vessel formation, VEGFR2 is a critical player. Therefore, inhibiting VEGFR2 is an effective way to target angiogenesis in cancer treatment. The aim of our research was to find new VEGFR-2 inhibitors by performing a virtual screening of 13313 from African natural compounds using different in silico techniques. Using molecular docking calculations and ADMET properties, we identified four compounds that exhibited a binding affinity ranging from -11.0 kcal/mol to -11.5 Kcal/mol when bound to VEGFR-2. These four compounds were further analyzed with 100 ns simulations to determine their stability and binding energy using the MM-PBSA method. After comparing the compounds with Regorafenib, a drug approved for anti-angiogenesis treatment, it was found that all the candidates (EANPDB 252, NANPDB 4577, and NANPDB 4580), with the exception of EANPDB 76, could target VEGFR-2 similarly effectively to Regorafenib. Therefore, we recommend three of these agents for anti-angiogenesis treatment because they are likely to deactivate VEGFR-2 and thus inhibit angiogenesis. However, it should be noted that the safety and suitability of these agents for clinical use needs further investigation, as the computer-assisted study did not include in vitro or in vivo experiments.

In silico design of novel CDK2 inhibitors through QSAR, ADMET, molecular docking and molecular dynamics simulation studies.

The present study aims to investigate about the quantitative structure-activity relationship (QSAR) of a series of Thiazole derivatives reported as anticancer agents (hepatocellular carcinoma), using principally the electronic descriptors calculated by the DFT method and by applying the multiple linear regression method. The developed model showed good statistical parameters (R2 = 0.725, R2adj = 0.653, MSE = 0.060, R2test = 0.827, Q2cv = 0.536). The energy EHOMO orbital, electronic energy (TE), shape coefficient (I), number of rotatable bonds (NROT), and index of refraction (n) were revealed to be the main descriptors influencing the anti-cancer activity. Further, new Thiazole derivatives have been designed and their activities and pharmacokinetic properties have been predicted using the validated QSAR model. The designed molecules were then assessed to molecular docking (MD), and molecular dynamic (MDs) simulation accompanied by the calculation of the binding affinity using MMPBSA script according to 100 ns a simulation trajectory, to study both their affinity and their stability towards CDK2 as a target protein for the cancer disease treatment. This research concluded with the identification of four new CDK2 inhibitors which are A1, A3, A5, and A6 showing good pharmacokinetic properties. The MDs results revealed that the newly designed compound A5 remained stable in the active center of the discovered CDK2 protein, indicating its potential as a novel inhibitor for the treatment of hepatocellular carcinoma. The current findings may eventually contribute to the development of robust CDK2 inhibitors in the future.Communicated by Ramaswamy H. Sarma.

Host Cell Proteases Mediating SARS-CoV-2 Entry: An Overview.

The outbreak of the SARS-CoV-2 virus in late 2019 and the spread of the COVID-19 pandemic have caused severe health and socioeconomic damage worldwide. Despite the significant research effort to develop vaccines, antiviral treatments, and repurposed therapeutics to effectively contain the catastrophe, there are no available effective vaccines or antiviral drugs that can limit the threat of the disease, so the infections continue to expand. To date, the search for effective treatment remains a global challenge. Therefore, it is imperative to develop therapeutic strategies to contain the spread of SARS-CoV-2. Like other coronaviruses, SARS-CoV-2 invades and infects human host cells via the attachment of its spike envelope glycoprotein to the human host cell receptor hACE2. Subsequently, several host cell proteases facilitate viral entry via proteolytic cleavage and activation of the S protein. These host cell proteases include type II transmembrane serine proteases (TTSPs), cysteine cathepsins B and L, furin, trypsin, and Factor Xa, among others. Given the critical role of the host cell proteases in coronavirus pathogenesis, their inhibition by small molecules has successfully targeted SARS-CoV-2 in vitro, suggesting that host cell proteases are attractive therapeutic targets for SARS-CoV-2 infection. In this review, we focus on the biochemical properties of host cell proteases that facilitate the entry of SARS-CoV-2, and we highlight therapeutic small molecule candidates that have been proposed through in silico research.

Function of selected natural antidiabetic compounds with potential against cancer via modulation of the PI3K/AKT/mTOR cascade.

Diabetes mellitus (DM) is a metabolic disorder with growing global incidence, as 387 million people were diagnosed in 2014 with an expected projection of 642 million in 2040. Several complications are associated with DM including heart attack, stroke, kidney failure, blindness, and cancer. The latter is the second leading cause of death worldwide accounting for one in every six deaths, with liver, pancreas, and endometrium cancers are the most abundant among patients with diabetes. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a vital role in developing a wide array of pathological disorders, among them diabetes and cancer. Natural secondary metabolites that counteract the deleterious effects of reactive oxygen species (ROS) and modulate PI3K/Akt/mTOR pathway could be a promising approach in cancer therapy. Here, 717 medicinal plants with antidiabetic activities were highlighted along with 357 bioactive compounds responsible for the antidiabetic activity. Also, 43 individual plant compounds with potential antidiabetic activities against cancer via the modulation of PI3K/Akt/mTOR cascade were identified. Taken together, the available data give an insight of the potential of repurposing medicinal plants and/or the individual secondary metabolites with antidiabetic activities for cancer therapy.

Pea (Pisum sativum) peel extract attenuates DOX-induced oxidative myocardial injury.

The goal of this work aimed to evaluate the protective effects of pea (Pisum sativum) peels extract versus doxorubicin-induced oxidative myocardial injury in male mice. The mice were divided into seven groups (n = 7): (I) control group; (II) P. sativum 250 group; (III) P. sativum 500 group; (IV) DOX (3 times alternately of 2.5 mg/kg/week, i.p. for a continuous two-week period) group; (V) Vit. E 100 + DOX group; (VI) P. sativum 250 + DOX group, and (VII) P. sativum 500 + DOX group). Twenty polyphenolic compounds, mainly flavonoid glycosides such as quercetin, kaempferol apigenin, and phenolics compounds were characterized by LC-MS/MS analysis in the examined extract. DOX administration elevated the activities of serum biomarkers of myocardial dysfunction (ALT, AST, ALP, LDH, troponin, CPK, and CK-MB), lipid profile, and proinflammatory cytokines. Also, it decreased cardiac antioxidants (GSH, SOD, GPX, CAT) and increased myocardial markers of oxidative stress (NO and MDA) and inflammatory marker (MPO). As well as it downregulated and upregulated the Bcl-2 (anti-apoptotic gene) and the Bax (pro-apoptotic gene) expressions, respectively. Pre-treatment of DOX-exposed mice with P. sativum or vitamin E (as a reference protective antioxidant) alleviated the changes dose-dependently via DOX-induced cardiotoxicity. These data show that P. sativum has a cardio-protective impact against DOX-induced cardiomyocyte damage in mice via boosting endogenous antioxidants, decreasing inflammation, and regulating BcL-2 and Bax apoptosis pathway, which might be related to the presence of flavonoid glycosides. P. sativum peels are a by-product that could be suggested for further screening as a possible new candidate for therapeutic use.

Syzygium jambos extract mitigates pancreatic oxidative stress, inflammation and apoptosis and modulates hepatic IRS-2/AKT/GLUT4 signaling pathway in streptozotocin-induced diabetic rats.

The protective effect of Syzygium jambos (SJ) bark extract against streptozotocin-induced diabetes was tested in rats. Animals were treated with 100 or 200 mg/kg of the extract or glibenclamide, 0.5 mg/kg per os, once daily: started 2 days before streptozotocin (STZ) injection and lasted for 14 days after STZ injection. The effect of the extract was also evaluated on normal rats in comparison with glibenclamide. Diabetic animals showed an elevated blood glucose level, positive glycosuria, elevated fructosamine, pancreatic malondialdehyde, pancreatic TNF-a, and pancreatic caspase-3 levels and decreased serum insulin, pancreatic IL-10, pancreatic BCL-2, reduced glutathione (GSH), liver insulin substrate-2, liver phosphorylated protein kinase B (p-AKT) and liver glucose transporter 4 (GLUT4) levels. Histopathological examination of diabetic rats revealed islets destruction and vacuolation and collagen fibers deposition. All these changes were mitigated dose dependently by the extract. The high dose of the extract exerted comparable effects with glibenclamide in most studied parameters. These results indicated the protective role of SJ against the STZ diabetogenic action. In the pancreatic and hepatic tissue of diabetic rats, SJ effectively recovered pancreatic cells by reducing hyperglycemia through activating endogenous antioxidants, dynamic insulin production, and suppressing inflammation and apoptosis. The observed results might be attributed to the existence of 10 secondary metabolites as annotated by LC-MS. Taken together, S. jambos is a potential candidate for further studies to confirm its activities as a therapeutic agent for diabetic patients.

Potamogeton perfoliatus L. Extract Attenuates Neuroinflammation and Neuropathic Pain in Sciatic Nerve Chronic Constriction Injury-Induced Peripheral Neuropathy in Rats.

Sciatic nerve injury is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous systems. In our previous work, Potamogeton perfoliatus L. displayed anti-inflammatory, antipyretic and analgesic properties, predominantly via the inhibition of COX-2 enzyme and attenuation of oxidative stress. Herein, we extended our investigations to study the effects of the plant's extract on pain-related behaviors, oxidative stress, apoptosis markers, GFAP, CD68 and neuro-inflammation in sciatic nerve chronic constriction injury (CCI) rat model. The levels of the pro-inflammatory marker proteins in sciatic nerve and brainstem were measured with ELISA 14 days after CCI induction. Pretreatment with the extract significantly attenuated mechanical and cold allodynia and heat hyperalgesia with better potential than the reference drug, pregabalin. In addition, CCI lead to the overexpression of prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), tumor necrosis alpha (TNFα), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and NADPH oxidase-1 (NOX-1) and decreased the catalase level in sciatic nerve and brainstem. The observed neuro-inflammatory changes were accompanied with glial cells activation (increased GFAP and CD68 positive cells), apoptosis (increased Bax) and structural changes in both brainstem and sciatic nerve. The studied extract attenuated the CCI-induced neuro-inflammatory changes, oxidative stress, and apoptosis while it induced the expression of Bcl-2 and catalase in a dose dependent manner. It also decreased the brainstem expression of CD68 and GFAP indicating a possible neuroprotection effect. Taking together, P. perfoliatus may be considered as a novel therapy for neuropathic pain patients after performing the required clinical trials.

New antibacterial peptide derived from bovine hemoglobin.

Peptic digestion of bovine hemoglobin at low degree of hydrolysis yields an intermediate peptide fraction exhibiting antibacterial activity against Micrococcus luteus A270, Listeria innocua, Escherichia coli and Salmonella enteritidis after separation by reversed-phase HPLC. From this fraction a pure peptide was isolated and analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS). This peptide correspond to the 107-136 fragment of the alpha chain of bovine hemoglobin. The minimum inhibitory concentrations (MIC) towards the four strains and its hemolytic activity towards bovine erythrocytes were determined. A MIC of 38 microM was reported against L. innocua and 76 microM for other various bacterial species. This peptide had no hemolytic activity up to 380 microM concentration.