A sustainable and versatile multicomponent protocol has been established for the synthesis of pyrido[4,5-d]pyrimidine derivatives employing caffeine-HNO3 as a recyclable, metal-free catalyst under mild ethanolic conditions. The strategy enables rapid access to the target fused heterocycles in consistently high yields with concise reaction durations, while avoiding harsh reagents and complex purification steps. The catalyst was comprehensively characterized using FT-IR, NMR, XRD, SEM, EDS, BET surface area analysis, and TGA. It was successfully reused over multiple cycles with minimal loss of activity, confirming its efficiency and operational simplicity. The greenness of the protocol was further validated by eco-metrics, highlighting its potential as an environmentally benign route. The synthesized compounds were subjected to preliminary biological screening, which demonstrated notable antibacterial activity and measurable cytotoxicity. The in silico studies including molecular docking, pharmacokinetics, and ADMET predictions supported the experimental findings and revealed promising drug-like properties. Collectively, this work presents a practical, eco-friendly, and scalable approach for the construction of fused heterocyclic scaffolds with significant medicinal relevance.

An environmentally sustainable and efficient synthesis of 1,4-bis(1H-benzo[d]imidazol-2-yl)benzene (TEE) is reported using terephthalaldehyde sodium bisulfite and o-phenylenediamine, with ethanol as an optimal green solvent. Microwave-assisted conditions significantly enhance reaction efficiency, affording high yields under mild conditions. Structural integrity and phase purity were confirmed by spectroscopic (NMR, FTIR, HRMS) and PXRD analyses. Density functional theory (DFT) calculations, supported by potential energy surface (PES) analysis, identify the anti-conformation as the most stable geometry. Frontier molecular orbital and UV–Vis analyses reveal effective π-electron delocalization, with a dominant π→π* transition at 343.9 nm and direct and indirect optical band gaps of 5.62 and 4.98 eV, respectively. Thermal studies indicate good stability. Notably, TEE exhibits significant antimicrobial activity, particularly against Pseudomonas aeruginosa, which is rationalized by molecular docking studies showing strong interactions with D-Ala-D-Ala carboxypeptidase and LasB elastase. Overall, this study establishes a clear structure–property–activity relationship, highlighting TEE as a promising heterocyclic scaffold for pharmaceutical and materials applications.

Mesalazine (MES) is a first-line therapy for inflammatory bowel disease (IBD); however, its clinical use is limited by variable patient response, intolerance, and reduced efficacy in severe cases. To address these challenges, we have designed and evaluated seventeen MES derivatives (M1–M17) using a comprehensive in silico strategy. Density functional theory with the B3LYP/6-311++G(d,p) basis set was employed to optimize geometries and explore electronic structure, stability, and reactivity. Structural characterization was further supported by FTIR and UV–visible spectral analysis. Molecular docking against five key IBD-associated targets (TNF, NOD2, ATG16L1, IL23R, and IL6) reveled that M1, M5–M8, M10, M11, M14, M16, and M17 showed stronger binding affinities than MES, where the M6 and M8 showed the strongest binding affinity. MES was more toxic towards the human body, although some of its derivatives were less toxic compared to MES, while M8 demonstrated an overall improved ADMET profile as an IBD medication. Molecular dynamics simulations of both M8–NOD2 and MES–NOD2 complexes revealed stable behavior in each system; however, M8 reduced structural fluctuations, flexibility, and solvent exposure, whereas MES promoted a more compact and conformationally restricted state, indicating distinct stabilization mechanisms, with M8 demonstrating superior dynamic control. Collectively, these findings identify M8 as a promising drug candidate for IBD, warranting further experimental validation through in vitro and in vivo studies.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health concern, necessitating the development of new and effective therapeutic agents. In this study, a novel Schiff base, (E)-N'-(2-hydroxybenzylidene)-2-((4-methylbenzyl)oxy)benzohydrazide (HL), was synthesized via condensation reaction and characterized using FTIR, UV-Vis, 1H NMR, mass spectrometry, and single-crystal X-ray diffraction, supported by DFT calculations. Hirshfeld surface analysis revealed dominant H & ctdot;H interactions (49.2%) along with significant pi-pi stacking contributions, indicating a stable crystal packing environment. The HOMO-LUMO energy gap (4.092 eV) suggests appreciable chemical reactivity, while the Gibbs free energy (Delta G = -1185.555 kcal/mol) indicates favorable binding potential with biological targets. MEP and NPA analyses identified carbonyl and hydroxyl oxygen atoms as key electrophilic sites. NCI-RDG analysis confirmed stabilization through hydrogen bonding and van der Waals interactions. The NLO analysis of HL shows a significantly enhanced first hyperpolarizability (beta tot = 137 & times; 10-31 esu), about 17.56 times higher than that of urea and comparable to paranitroaniline, indicating strong second-order NLO activity. Increased polarizability, dipole moment, and anisotropy across solvents further confirm efficient intramolecular charge transfer and highlight its potential for advanced photonic applications. PASS prediction suggested antitubercular activity, supported by molecular docking studies showing stronger binding affinity toward InhA (PDB IDs: 2IDZ and 4TRN) compared to isoniazid. Molecular dynamics simulations confirmed stable protein-ligand interactions, while ADMET analysis indicated favorable pharmacokinetic properties. Overall, HL demonstrates promising dual functionality as a potential antitubercular agent and nonlinear optical material for future biomedical and optoelectronic applications.

Human colon cancer and prostate cancer are the most common malignancy globally. Despite the availability of many treatments, resistance to traditional medicines, such as chemotherapy and radiotherapy, remains a severe obstacle in cancer treatment. Hence, searching for new therapeutic options is of utmost priority. The present investigation evaluates the in-silico and in-vitro anticancer potential of phytochemicals of Piper chaba. The cytotoxicity results demonstrated that the plant extract exhibited significant anticancer activity, with IC50 values of 12.66 ± 0.25 µg/mL for HCT-116 and 19.49 ± 0.37 µg/mL for DU-145. Molecular docking and molecular dynamics simulations were performed to explore the interaction of potential drug targets with the phytochemicals. Subsequently, pharmacokinetic parameters calculations were performed to evaluate the drug-likeness. Piperine exhibits the highest binding affinity for vascular endothelial growth factor receptor-2 (VEGFR2) protein with a docking score of -9.71 kcal/mol. Sylvatine had a greater binding affinity for human epidermal growth factor receptor 3 (HER3) protein than the other phytochemicals. Isopiperine, chabamide, Piperlonguminine, Santamarine and Versalide only exhibited ligand activity for human IKK beta protein (inhibitor of kappa B kinase). Additionally, a principal component analysis was performed to strengthen the investigation's scope. These proposed phytochemicals are reported to possess potential VEGFR2, HER2 and human IKK beta inhibition. The best phytochemical hits have excellent binding affinity and hold a massive anticancer potential, opening up new avenues for prospective future investigations in cancer treatment.

Cancer is a significant health and economic concern worldwide. Prostate cancer (PC) ranks as the fourth leading cause of global death and is the second most prevalent malignancy in males. Androgens are essential for the progress and growth of the prostate gland. PC is caused by androgens binding to receptors, which activates genes that promotes the development of PC. Nilutamide (NLM) is an antiandrogen medicine used in the treatment of PC. However, throughout treatment, it induces various toxicities and leads to resistance in patients. The objective of the work was to designed and evaluated safer NLM analogues using computational approaches with optimized pharmacokinetic profiles and less toxicity. Newer bioisosteres of the designed NLM analogues and their ADMET scores were calculated using the MolOpt and ADMETlab 3.0 tools, respectively. We conducted docking investigations of the designed ligands using AutoDock Vina software. The MolOpt web server produces 1575 bioisosteres of NLM using the scaffold transformation method. The 47 bioisosteres were selected based on pharmacokinetic profiles, drug likeness (DL) and drug score (DS) prediction scores and were determined to be optimum to excellent in comparison to NLM. The analogues NLM28, NLM31, NLM34, NLM38, NLM40, NLM44, NLM45, and NLM47 exhibited favorable interactions and docking scores with the protein (PDB ID: 2AM9). The molecular dynamics (MD) simulation results revealed that the NLM34 and NLM40 complexes were found stable during the 100 ns run. The findings indicate that the NLM analogues, particularly NLM34 and NLM40 have the potential to be used as promising antiandrogen agents for PC therapy.

Inhibiting c-Abl kinase pharmacologically is necessary because of its role in oxidative stress and neurodegeneration. When activated, it causes the accumulation of α-synuclein and dopaminergic neuron damage, leading to Parkinson’s disease (PD). Reports of the effectiveness of c-Abl inhibitors repurposed for PD were accompanied by both hope and numerous concerns. Therefore, there is an urgent need for alternative c-Abl inhibitors. We employed a machine-learning-based QSAR model to identify potential actives against c-Abl kinase, screening selected FDA-approved and phase 1 drugs; optimizing the compounds’ structures through bioisostere replacement; conducting molecular docking algorithms (HTVS, SP, XP, and Prime’s Molecular Mechanics with Generalized Born and Surface Area (Prime-MMPBSA)); in silico pharmacokinetic profiling; and structural stability and dynamics studies for 200 ns. From 3605 drugs and 1456 bioisosteres, two bioisosteres of indobufen (indobufen 25 and 22) showed promising potential against c-Abl kinase. As the two bioisosteres returned the closest docking scores (14.880 and − 14.265 kcal mol−1, respectively) to the control drug (nilotinib, − 15.312 kcal mol−1), the Prime-MMGBSA calculations returned − 81.92 and − 84.07 kcal mol−1, respectively; MMPBSA calculations after a 200-ns MD simulation run returned − 48.20 ± 3.69 kcal mol−1 and − 49.94 ± 3.05 kcal mol−1, respectively. This indicates their stability compared to other test compounds, as supported by the RMSD, RMSF, PCA, and DCCM results. Finally, both bioisosteres interacted with MET 318, ASP 381, TYR 253, ALA 269, and PHE 317 in the c-Abl active site. We present these bioisosteres as potential candidates for the treatment or management of PD targeting c-Abl kinase. However, in vitro and in vivo experiments to validate the findings are urgently required.

BACKGROUND:Inflammation is a natural process; however, chronic inflammation may result in numerous health issues. Etoricoxib (ETX), a selective cyclooxygenase-2 (COX-2) inhibitor, serves as an anti-inflammatory agent for various types of arthritis. However, prolonged use of ETX is associated with several adverse effects, including cardiovascular toxicity. OBJECTIVE:The current research aims to design an analogue of ETX having superior pharmacokinetic properties and safer toxicological profiles employing the bioisosteric approach. METHODS:The bioisosteres of various groups in ETX were produced utilizing the MolOpt online tool, resulting in the generation of novel ETX analogues. The pharmacokinetics (ADME) and toxicological profiles of the generated analogues were calculated by ADMETLab 3.0 server. The druglikeness (DL) and drugscore (DS) were calculated using OSIRIS property explorer (PEO). The molecular docking analysis of the ETX analogues against the target protein (PDB ID: 5KIR) was carried out using AutoDock Vina, and their results were visualized by Discovery Studio 2021. Molecular Dynamics (MD) simulation of the top three complexes was conducted using the Schrödinger suite. Binding free energy for the A098-5KIR, A188-5KIR, and D121- 5KIR complexes was conducted using MM-GBSA/PBSA method. RESULTS:A total of 1200 ETX bioisosteres were produced; among them, 51 were screened on the basis of ADMET profile, DL, and DS scores and selected for the docking study. A docking study revealed that 12 analogues show good interactions and docking scores. Furthermore, the molecular dynamics simulation of ligands A098, A188, and D121 demonstrated stability throughout the 100 ns simulation period. CONCLUSION:The findings of the ADMET study, DL, DS, docking study, MD simulation, and binding free energy calculation indicate that the analogues A098, A188, and D121, which are bioisosteres of ETX, may serve as potential anti-inflammatory agents for inflammation-related disorders.

This study aims to identify potential DYRK1A inhibitors from a curated database and utilize a QSAR model to predict the bioactivity of drug compounds in inhibiting the enzyme involved in tau protein oligomerization, a key process in AD pathology. 192 compounds were sourced from the SuperNatural 3.0 database and docked against DYRK1A using Maestro 12.5. The top five lead compounds and the reference drug Abemaciclib underwent ADMET profiling via the AI Drug Lab Server and a 200 nanosecond molecular dynamics simulation using Desmond. A machine learning-based Quantitative Structure-Activity Relationship (QSAR) analysis was then performed to predict their biological activity based on pIC50 values. The top five compounds, identified as 45,934,388, CNP0344929, CNP0360040, CNP0309850, and CNP0426983, demonstrated binding affinities of -13.337, -12.746, -11.712, -11.656, and - 11.416 kcal/mol, respectively, outperforming Abemaciclib (-6.528 kcal/mol). None of the compounds violated Lipinski's Rule of Five, and all exhibited favorable ADMET profiles, including optimal blood-brain barrier penetration and structural stability. The QSAR model successfully predicted the pIC50 values of the hit compounds (6.16, 5.758, 5.752, 6.003, 5.982), comparable to Abemaciclib (6.32). These findings highlight five promising DYRK1A inhibitors with potential therapeutic applications for AD.

BACKGROUND:Oxidative stress is strongly linked to neurodegeneration through the activation of c-Abl kinase, which arrests α-synuclein proteolysis by interacting with parkin interacting substrate (PARIS) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This activation, triggered by ataxia-telangiectasia mutated (ATM) kinase, leads to dopaminergic neuron loss and α -synuclein aggregation, a critical pathophysiological aspect of Parkinson's disease (PD). To halt PD progression, pharmacological inhibition of c-Abl kinase is essential. Despite three generations of tyrosine kinase inhibitors (TKIs) being explored for PD treatment, they present significant concerns including poor blood-brain barrier penetration, off-target effects, and severe side effects. Notably, there are currently no FDA-approved c-Abl kinase inhibitors in clinical usage for PD treatment, highlighting the urgent need for potent, safe, and cost-effective alternatives. OBJECTIVE:This study aims to identify potential c-Abl kinase inhibitors from plant-derived compounds with reported anti-Parkinson's potential and their derivatives using molecular docking, molecular dynamics simulations (MDS), and in silico pharmacokinetics and toxicity profiling. METHODS:Seventy-eight compounds sourced from literature were docked against c-Abl kinase using Maestro 12.5. The top three hit compounds, along with nilotinib (control drug), were subjected to drug-likeness, ADMET profiling using the AI Drug Lab server and 100 ns MDS using Desmond. RESULTS:Amburoside A, diarylheptanoid MS13, and dimethylaminomethyl-substituted-curcumin showed binding affinities close to nilotinib, with values of -12.615, -12.556, and -11.895 kcal/mol respectively, compared to nilotinib's -16.826 kcal/mol. The three plant-derived compounds exhibited excellent structural stability and favorable ADMET profiles, including optimal blood-brain barrier permeation. CONCLUSION:The three hit compounds identified in this study show potential as c-Abl kinase inhibitors. Given the absence of FDA-approved c-Abl kinase inhibitors for PD, these findings are significant as they could contribute new therapeutic options for the treatment and management of PD. However, further in vitro and in vivo experiments are necessary to validate these findings.

Background: Acquired Immunodeficiency Syndrome (AIDS) is a critical global health issue caused by the human immunodeficiency virus (HIV). It has different strains and subtypes; among these, Subtype C accounts for higher infection rates than others. Despite its high prevalence, the molecular interactions with host receptors, specifically CD4, have not yet been explored. Methods: This study investigates the molecular interactions between HIV subtype C and the CD4 receptor via docking and dynamics approach. Four HIV targets were examined, and their structure was modelled. Subsequently, these models were docked with the CD4 to analyze their binding interaction. The stability was examined over 200 simulations via Desmond software, and trajectories were analyzed, followed by Root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the radius of gyration (Rg), PCA (principal component analysis), etc., to assess their stability and interaction dynamics. Results: The four target structures were modelled, and their quality was validated. Further, the docking analysis with CD4 revealed that the Envelope glycoprotein has-13.6 kcal/mol, protease has-11.2 kcal/mol, Reverse transcriptase has-12.4 kcal/mol, and integrase has-13.1 kcal/mol binding affinity towards it, followed by the number of hydrogen bond, such as 9, 6, 11, 6. The simulation over 200 ns demonstrated that the average RMSD for each complex started stabilizing within the 0.9 & Aring;- 3.4 & Aring;, followed by 25-50 ns, whereas the RMSF, Rg and PCA revealed the relative compactness and flexibility varied across different viral targets. Conclusions: The study successfully identified the interactive residues of HIV subtype C toward the CD4 receptor. The binding affinities and stability data provide valuable insights into Subtype C's molecular interactions with the host, and these findings underscore the potential for developing treatments that disrupt these interactions to combat HIV more effectively.

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a major challenge to global health. Targeting the main protease of the virus (Mpro), which is essential for viral replication and transcription, offers a promising approach for therapeutic intervention. In this study, advanced computational techniques such as molecular docking and molecular dynamics simulations were used to screen a series of antiviral compounds for their potential inhibitory effect on the SARS-CoV-2 Mpro. A comprehensive analysis of compounds from the ChemDiv and PubChem databases was performed. The physicochemical properties, pharmacokinetics, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles were evaluated to determine drug similarity and safety. Compound 4896 − 4038 proved to be the most promising candidate. It exhibited a favorable balance between molecular weight (491.06) and lipophilicity (logP 3.957), high intestinal absorption (92.119%), and broad tissue distribution (VDss of 0.529), indicating good oral bioavailability and therapeutic potential. Molecular docking studies showed that 4896 − 4038 has a strong binding affinity to the active site of Mpro and forms key interactions, such as hydrogen bonds, carbon-hydrogen bonds, pi-sulfur, and multiple van der Waals and pi-pi stacked bonds. The binding energy was comparable to that of the reference drug X77, indicating potential efficacy. Molecular dynamics simulations over 300 ns confirmed the stability of the Mpro/4896 − 4038 complex of protein-ligand. Free energy landscape mapping and MM/PBSA calculations further substantiated the favorable binding and stability of the complex. Importantly, 4896 − 4038 exhibited a comparatively favorable safety profile. In summary, compound 4896 − 4038 shows significant potential as a potent SARS-CoV-2 Mpro inhibitor, combining potent inhibitory activity with favorable pharmacokinetic and safety profiles. These results support the further development of 4896 − 4038 as a promising therapeutic agent in the fight against COVID-19 that warrants experimental validation and clinical investigation.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the COVID-19 pandemic, remains a major global health concern due to the lack of a universally effective treatment. According to the World Health Organization (2025), global SARS-CoV-2 activity has been increasing since mid-February 2025, with test positivity rates reaching levels not observed since July 2024, further underscoring the urgent need for effective antiviral strategies. In the present investigation, a structure-based virtual screening methodology was utilized to evaluate 3125 phytochemicals sourced from 311 antiviral Indian medicinal plants listed in the IMMPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database. The selected compounds were modeled and subjected to virtual screening targeting the SARS-CoV-2 main protease (Mpro), a critical enzyme involved in viral replication processes. Nelfinavir, a well-established Mpro inhibitor, served as the reference. Theasinensin B (−8.974 kcal/mol) and Cyanidin 3-O-rutinoside (−7.470 kcal/mol) exhibited superior docking scores compared to Nelfinavir (−6.139 kcal/mol). These findings were validated by MM-GBSA binding free energy estimations and 200 ns molecular dynamics (MD) simulations. Theasinensin B showed consistent and stable interactions across the simulation trajectory, particularly with key residues ASP153, ARG105, and GLN110, while Cyanidin 3-O-rutinoside displayed moderate interactions. Furthermore, density functional theory (DFT) analysis was conducted on the top hits to assess their electronic properties and chemical reactivity, providing additional insight into their stability and potential inhibitory efficacy. This study highlights the therapeutic promise of phytochemicals as potent inhibitory candidates targeting SARS-CoV-2, emphasizing the value of phytochemical libraries and computational screening as rapid tools for identifying antiviral candidates during public health crises. However, it is limited by the absence of ADME considerations and further experimental validation, which are warranted to substantiate the clinical applicability of these findings.

Alzheimer's disease (AD), characterized by cognitive decline, behavioral changes, and amnesia, ultimately leads to dementia in older people. Despite decades of study, there is still no effective way to prevent, retard, or reduce the symptoms of AD. In this paper, we report indole-based heterocyclic conjugates as cholinesterase inhibitors. Compounds 14c (IC50s AChE = 0.30 mu M; BuChE = 10.16 mu M) and 14h (IC50s AChE = 0.58 mu M; BuChE = 15.13 mu M) display efficacy against both AChE and BuChE. These derivatives did not exhibit toxicity against the HEK293 and SH-SY5Y cell lines. Docking analysis demonstrated better binding affinity of these compounds (docking score, 14c = -9.06 kcal/mol; 14h = -9.03 kcal/mol) with recombinant human acetylcholinesterase (PDB ID:4EY7) as compared to the reference drug donepezil (-8.52 kcal/mol). Molecular dynamics analysis demonstrated better MMGBSA binding free energy of these compounds (14c = -33.10 kcal/mol; 14h = -36.64 kcal/mol) with recombinant human acetylcholinesterase as compared to the reference drug donepezil (-32.20 kcal/mol). These compounds bind in the active site of acetylcholinesterase and maintain stability similar to donepezil during a 200 ns MD simulation. Moreover, these compounds exhibit recognizable ADME characteristics.

2-Aminobenzothiazoles constitute a significant class of heterocyclic compounds, notable for their extensive pharmacological significance. While their synthesis has typically utilized phenyl isothiocyanate, the potential of alternative isothiocyanates remains largely unexplored. This research presents an alternative synthetic route for the preparation of known substituted 2-aminobenzothiazoles, N-(propan-2-yl)-1,3-benzothiazol-2-amine (SISI) and N-(prop-2-en-1-yl)-1,3-benzothiazol-2-amine (SIAL) using isopropyl isothiocyanate (IPI) and allyl isothiocyanate (AITC) as underutilized precursors under mild copper-catalyzed conditions. Structural elucidation was conducted using FTIR, HRMS, NMR, and single-crystal XRD. DFT results (B3LYP/6-31G(d,p) level) demonstrated a strong correlation with experimental crystallographic data. Hirshfeld surface analysis identified key intermolecular interactions that contribute to crystal packing stability. The antimicrobial assay revealed substantial inhibitory effects against Gram -ve and Gram +ve strains for bacteria along with fungal species, with Escherichia coli exhibiting particular sensitivity. In silico ADME profiling suggested promising pharmacokinetic properties, including high GI and BBB permeability. Molecular docking results indicated strong binding interactions with bacterial DNA gyrase (6F86) and topoisomerase IV (1s14), with SISI and SIAL demonstrating higher binding affinities for topoisomerase IV than streptomycin (binding affinity SISI; -6.0 kcal mol-1, SIAL; -5.8 kcal mol-1, streptomycin; -5.5 kcal mol-1). The enhanced interaction suggests a potential mechanism for their antimicrobial activity, highlighting the synthetic and biological relevance of IPI and AITC as alternative precursors in aminobenzothiazole chemistry, through an efficient and comparative synthetic route for known derivatives.

Introduction Heterogeneous Acute Myeloid Leukemia (AML) causes substantial worldwide morbidity and death. AML is characterized by excessive proliferation of immature myeloid cells in the bone marrow and impaired apoptotic regulator expression. B-Cell Lymphoma 2 (BCL-2), an anti-apoptotic protein overexpressed in AML, promotes leukemic cell survival and chemoresistance. Thus, reducing BCL-2 may treat AML. Anticancer activities are found in Aloe barbadensis Miller (Aloe vera). Thus, this work used molecular modeling to assess Aloe vera bioactive chemicals as BCL-2 inhibitors. Methods Selected bioactive compounds from Aloe vera was docked against BCL-2 using AutoDock Vina. drug-likeness, pharmacokinetics, and toxicity profiling was carried out using SwissAdme and ADMETSar servers. Finally, the two most promising compounds were subjected to 100 ns molecular dynamics (MD) simulation in Desmond software. Results The Binding energies of the compounds were found to be between -6.7 to -8.7 kcal/mol, with campesterol and a-tocopherol returning the least binding energy. Furthermore, both compounds displayed good druglikeness, and ADMET profiles. In addition, they maintained stable nature in the binding pocket of BCL-2 during the 100 ns MD simulation. Conclusion Campesterol and α-tocopherol are promising BCL-2 inhibitors that might become effective anti-leukemic therapies with additional in vitro and in vivo research.

IntroductionOne of the foremost contributors to mortality worldwide is cancer. Chemotherapy remains the principal strategy for cancer treatment. A significant factor leading to the failure of cancer chemotherapy is the phenomenon of multidrug resistance (MDR) in cancer cells. The primary instigator of MDR is the over expression of P-glycoprotein (P-gp), a protein that imparts resistance and facilitates the ATP-dependent efflux of various anticancer agents. Numerous efforts have been made to inhibit P-gp function with the aim of restoring the effectiveness of chemotherapy due to its broad specificity. The main objective has been to create compounds that either serve as direct P-gp inhibitors or interact with cancer therapies to modulate transport. Despite substantial in vitro achievements, there are currently no approved drugs available that can effectively “block” P-gp mediated resistance. Cabozantinib (CBZ), a multi-kinase inhibitor, is utilized in the treatment of various carcinomas. CBZ has been shown to inhibit P-gp efflux activity, thereby reversing P-gp mediated MDR. Consequently, P-gp has emerged as a critical target for research in anti-cancer therapies.MethodsThe purpose of this study was to computationally identify new andsafer analogues of CBZ using bioisosteric approach, focusing on improved pharmacokinetic properties andreduced toxicity. The physicochemical, medicinal, and ADMET profiles of generated analogues were computed using the ADMETLab 3.0 server. We also predicted the drug likeness (DL) and drug score (DS) of analogues. The molecular docking studies of screened analogues against the protein (PDB ID: 3G5U) were conducted using AutoDock Vina flowing by BIOVIA Discovery Studio for visualizing interactions.Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite.Results and DiscussionThe docking scores for the ligands CBZ01, CBZ06, CBZ11, CBZ13, CBZ25, CBZ34, and CBZ38 ranged from −8.0 to −6.4 kcal/mol against the protein (PDB ID: 3G5U). A molecular dynamics (MD) simulation of CBZ01, CBZ13, and CBZ38 was conducted using the Schrödinger suite, revealing that these complexesmaintained stability throughout the 100 ns simulation.ConclusionAn integrated computational approach combining bioisosteric approach, molecular docking, drug likeness calculations, and MD simulations highlights the promise of ligands CBZ01 and CBZ13 as candidates for the development of potential anticancer agents for the treatment of various cancers.

As the HIV-based complication is still going on with the high infection and mortality rate, it requires a novel strategy to combat this infection due to the unavailability of proper therapeutic. Therefore, we utilize integrated immuno and bioinformatics approaches in this study to design a peptide vaccine against HIV infection by targeting its complete genome. The complete genome sequence was analyzed, and the potential B and T cells were predicted. Among the predicted epitopes, the promising ones were selected and further used with the adjuvant and linker to formulate a vaccine candidate. The vaccine was modeled, and its activity and stability towards the TLRs were analyzed via docking and dynamics (500ns). The vaccine-generated immune activity and expression via in-silico cloning were also evaluated. A total of 6 B cells, 7 CTL, and 6 HTL were identified as an immunodominant epitope and used for vaccine formulation. These epitopes were fused together via linkers, and their efficiency and constancy were enhanced with Adjuvant, PADRE epitope, and His-tag. Further, the formulated vaccine shows high population coverage and stable features based on the 2D and 3D assessments. The docking investigation demonstrated the strong activity of the vaccine towards the TLR2 and TLR3, having binding affinity − 10.8 kcal/mol-1 and − 15.8 kcal/mol-1, and also disclosed remarkable constancy based on the 500ns simulation period. The vaccine-assisted immune simulation and expression level in the vector revealed a robust immune response towards the host based on the vaccination and a significant expression level. Based on the integrated approach and validation steps, the overall finding suggests that the formulated vaccine may have strongly immunodominant properties and could combat the infection.

We propose a tuning-by-delay hypothesis to explain the hemispheric specialization of function that has intrigued psychologists, philosophers, neurologists and neuroscientists for decades. In the auditory domain, speech and melody processing are understood to be lateralized in the left and the right hemispheric brain areas, respectively. Thus, analogous to the notion of pleiotropy where one gene can influence two or three unrelated traits, there exists a shared structural connectome encompassing both hemispheres underlying speech and melody processing, which however gets segregated along left vs right hemispheres, respectively. Here, we demonstrate how empirical observations of hemispheric specialization of speech and melody are shaped by the computational time-scales of information integration in cortical networks. First, we demonstrate that context-specific causal outflow of information emerging from primary auditory cortices (PAC) drives the hemispheric specialization of speech and melody processing when human volunteers listened to a cappella songs placed within a delayed match to sample task while electroencephalogram (EEG) were recorded. Second, together with participant specific whole-brain connectome model guided by diffusion weighted imaging, we predicted individual specific lateralization indices of inflow in cortical sources - after rigorous source time series reconstruction of EEG spectra. High levels of accuracy in the prediction of laterality indices in the extended large-scale auditory related regions can be achieved after optimizing conduction speeds of information propagation over a neuro-oscillatory network - a novel way to interpret about the neural mechanisms. We demonstrate that parametric modulation of conduction speeds that effectively controls the transmission delays - a key metric for understanding information processing and control of any biological network. Thus, the transmission delay in turn, acts as the switch and triggered by the spectro-temporal complexity of the task context to select the geometry of lateralization.### Competing Interest StatementThe authors have declared no competing interest.