Vitamin B1 (thiamine) plays an important role in human metabolism. It is essential for the proper growth and development of the body and has a positive effect on the functioning of the digestive, cardiovascular, and nervous systems. Additionally, it stimulates the brain and improves the psycho-emotional state. In vivo, vitamin B1 occurs in free form as thiamine or as its ester with phosphate residue(s), i.e., as mono-, di-, or triphosphate. It has been proven that supportive therapy with vitamin B1 can not only provide neuroprotection but also has a positive effect on advanced neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Wernicke-Korsakoff syndrome, or Huntington's disease. This paper presents studies on the effect of free thiamine (T) and thiamine pyrophosphate (TPP) on the activity of acetylcholinesterase (AChE), which is an enzyme considered to play an important role in the therapies for neurodegenerative diseases, especially Alzheimer's disease. The mechanisms of action of these compounds as potential inhibitors of AChE were evaluated using both experimental (enzymatic activity) as well as computational (molecular docking, molecular dynamics simulations, and MM-GBSA calculations) methods. The results of the current study indicate a non-competitive type of enzyme inhibition, in contrast to the previously published works suggesting a competitive one.

Alzheimer's disease is a neurodegenerative disorder that impairs neurocognitive functions. Acetylcholinesterase, Butyrylcholinesterase, Monoamine Oxidase B, Beta-Secretase, and Glycogen Synthase Kinase Beta play central roles in its pathogenesis. Current medications primarily inhibit AChE but fail to halt or reverse disease progression due to the multifactorial nature of Alzheimer's. This underscores the necessity of developing multi-target ligands for effective treatment. This study investigates the potential of phytochemical compounds from Moroccan medicinal plants as multi-target agents against Alzheimer's disease, employing computational approaches. A virtual screening of 386 phytochemical compounds, followed by an assessment of pharmacokinetic properties and ADMET profiles, led to the identification of two promising compounds, naringenin (C23) and hesperetin (C24), derived from Anabasis aretioides. These compounds exhibit favourable pharmacokinetic profiles and strong binding affinities for the five key targets associated with the disease. Density functional theory, molecular dynamics simulations, and MM-GBSA calculations further confirmed their structural stability, with a slight preference for C24, exhibiting superior intermolecular interactions and overall stability. These findings provide a strong basis for further experimental research, including in vitro and in vivo studies, to substantiate their potential efficacy in Alzheimer's disease.

A series of 4-methylthiazole-2-amine derivatives (3a–3f, 6g–j and 7) were prepared via a Hantzsch-type multicomponent reaction and characterized by FT-IR, 1H-NMR and 13C-NMR spectroscopy techniques. The cytotoxic effects of the synthesized products on the chronic myeloid leukemia K562 and U937 cell lines were tested using the MTT assay. Compounds 3a, 3b, 3c, 6g, 6h and 6i exhibited high cytotoxic potential with IC50 values ranging from 1.5 to 5 0 µM, which showed a dose-dependent inhibition. Stable ligand–receptor interaction was observed by molecular docking studies against the chosen CML-associated proteins (2GQG, 5MO4, 2AZ5 and 5MAR) with the highest docking scores obtained for 6h and 6i (−8.37 and −8.97 kcal mol−1, respectively). Strong binding affinities (ΔG = −53.36 kcal mol−1) were confirmed by MM-GBSA calculations. Further, density functional theory (by using B3LYP/6-311G basic function set) was used to gain information on the electronic configurations, HOMO–LUMO gaps and charge distribution, which favored stability of the molecules and reactivity. The combined experimental and computational findings indicated that compounds 6h and 6i are potential scaffolds that can be used to develop new thiazole-based anticancer agents against chronic myeloid leukemia.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease marked by hepatic steatosis, inflammation, and fibrosis, with limited therapeutic options. This study introduces a novel PROTAC-based strategy for the selective degradation of apoptosis signal-regulating kinase 1 (ASK1), a key mediator of MASH pathology. We first developed dASK1 (35), a cereblon (CRBN)-based PROTAC, which successfully formed a stable ternary complex with ASK1, facilitating its rapid and sustained degradation via the ubiquitin-proteasome pathway. In vitro evaluations demonstrated potent ASK1 degradation in the 10-100 nM range (70% degradation at 100 nM) in HepG2 and HEK293A cell lines, validating the efficacy of dASK1 (35). To enhance the degradation mechanism and explore broader E3 ligase utility, we designed and synthesized dASK1-VHL (60), leveraging the von Hippel-Lindau (VHL) E3 ligase, known for its regulatory functions in hepatic physiology. We optimized the linker length through molecular docking and MMGBSA calculations, achieving efficient ASK1-VHL engagement and stable ternary complex formation. Detailed ADME and pharmacokinetic studies confirmed that dASK1-VHL (60) exhibited enhanced solubility, moderate clearance, and improved bioavailability, making it suitable for in vivo application. In an MCD diet-induced murine model of MASH, dASK1-VHL (60) effectively reduced ASK1 protein levels, suppressed p38 MAPK activation, and decreased hepatic lipid content, indicating significant therapeutic benefits. This work underscores the importance of rational PROTAC design, precise linker engineering, and innovative E3 ligase selection in optimizing target protein degradation. Our findings pave the way for developing VHL-based PROTACs, offering a novel therapeutic approach for metabolic and inflammatory liver diseases.

Background:Isoprenylcysteine carboxyl methyltransferase (ICMT) is an enzyme crucial for the post-translational processing of Ras oncoproteins. Pharmacological inhibition of ICMT can mislocalize Ras and disrupt oncogenic signaling, exhibiting anticancer effects. Radicicol (RAD) is a 14-membered resorcylic acid lactone biosynthesized by fungi and possesses diverse bioactivities.Objective:The current work explored RAD’s interaction with ICMT through molecular docking and molecular dynamics simulations, comparing Radicicol’s binding mode to that of the native ICMT ligand.Method:Docking simulations were performed using Glide XP mode, and binding energies were refined by MM-GBSA calculations. Molecular dynamics simulation of 100 ns was conducted to assess the binding stability of the Radicicol–ICMT complex using Desmond, with analysis of RMSD and protein–ligand interactions.Results:Molecular docking and molecular dynamics simulations revealed that RAD stably bound within the ICMT active site by bridging both the S-adenosylmethionine cofactor pocket and the hydrophobic prenyl substrate tunnel. Its key interactions included a persistent hydrogen bond with Val116 and an induced-fit engagement of Arg125, supporting a snug and stable RAD–ICMT complex.Conclusion:These computational insights suggested that RAD inhibited ICMT by dual-site binding, simultaneously occupying the cofactor and substrate pockets. Such a dual engagement could mislocalize prenylated proteins (like Ras) and represent a novel mechanism of action for RAD.

Cancer is a complex disease characterized by uncontrolled cell proliferation, often driven by dysregulated cyclin-dependent kinases (CDKs), particularly CDK2, which plays a crucial role in cell cycle progression. Aberrant CDK2 activity is associated with tumor growth and resistance to therapy, making CDK2 a promising therapeutic target. The main focus of this research is to integrate the multi-omics-based pan-cancer analysis of CDK2 to identify novel plant-derived inhibitors, bridging the prognostic and therapeutic relevance of CDK2 across various cancer types. In this study, to evaluate CDK2's expression, prognostic behavior, genetic alterations, and immune infiltrations, we performed pan-cancer analysis. The oncogenic analysis showed that CDK2 is significantly overexpressed in multiple tumor types and, in some cancers, which correlated with poor overall and disease-free survival, indicating its potential as a context-dependent prognostic biomarker. The involvement of CDK2 in key cell cycle and oncogenic pathways was investigated, highlighting its centrality in tumor proliferation networks. Additionally, cheminformatics and machine learning approaches were applied to screen phytocompounds from six medicinal plants, and the top phytocompounds (>pIC50 = 5.1) were then subjected to molecular docking, pharmacodynamics, pharmacokinetics, and dynamics simulation studies. Docking results revealed that withanolide M, withanolide K, and ergosterol showed the highest binding affinities against CDK2, with scores of −10.2, −10.1, and −9.9 kcal mol−1, respectively. These lead phytocompounds exhibited high potency, excellent pharmacokinetic properties, and minimal predicted toxicity as compared with the control inhibitor of CDK2. The binding stability of the protein–ligand complexes was confirmed by dynamic simulations along with MM-GBSA calculations, with the results supporting our previously reported affinity score. Therefore, these phytocompounds could be potential CDK2 inhibitors, warranting exploration in future cancer research. Furthermore, additional experimental and clinical validations are required to confirm the efficacy and efficiency of these potential lead compounds.

Based on the rational design of DNA intercalators and Topo-II inhibitors and taking into consideration the main pharmacophoric features of doxorubicin (Dox) as a reference standard, we theoretically designed novel substituted tetrahydropyrimidine analogues (T1–35). The designed analogues (T1–35) were investigated for their inhibitory potential towards the hybrid DNA and Topo-II target receptor using molecular docking. Interestingly, the theoretically designed analogue T30 with a 3,4,5-trimethoxy phenyl side chain was found to be the superior candidate, achieving a binding score of −7.06 kcal mol−1, compared with two reference standards, doxorubicin (Dox) and a co-crystal ligand (EVP). Moreover, the docked candidates (T30, Dox, and EVP) were further subjected to molecular dynamics simulations for 500 ns. Furthermore, MM-GBSA calculations showed that the target candidate (T30) achieved superior ΔG binding energy (−33.86 kcal mol−1) compared with Dox and EVP. Moreover, T30 was found to be the most promising candidate that could be conveniently synthesized based on its order in the chemical synthesis scheme. In addition, to evaluate the antiproliferative activity and scope of compound T30, we requested the National Cancer Institute (NCI) to test it against nine cancer cell types. Interestingly, compound T30 exhibited very strong antiproliferative activity with a mean GI% of 122% and a mean GI50 of 4.10 μM. It exhibited the highest anticancer activity towards all 59 cell lines. Moreover, the in vitro binding interaction of compound T30 with calf thymus DNA (ctDNA) was examined using various techniques, such as spectrofluorimetry, UV-vis spectrophotometry, viscosity measurements, ionic strength measurements, and thermodynamics to confirm its mechanism of action. Investigating the intermolecular binding interaction between small compounds and DNA can provide valuable insights for designing drugs with enhanced effectiveness and improved targeted activities.

The phosphorylation of residue T177 produces a significant effect on the conformational dynamics of CDK6. Gaussian accelerated molecular dynamics (GaMD) simulations followed by deep learning (DL) are applied to explore the molecular mechanism of the phosphorylation-mediated effect on the conformational dynamics of CDK6 bound by three inhibitors 6ZV, 6ZZ and 0RS, in which 6ZV and 6ZZ have been used to test clinical performance. The DL finds that the β-sheets, αC helix as well as the T-loop are involved in obvious differences of conformation contacts and suggests that the T-loop plays a key role in the function of CDK6. The analyses of free energy landscapes (FELs) reveal that the phosphorylation of T177 leads to alterations of the T-loop conformation and the results from principal component analysis (PCA) indicate that the phosphorylation affects the fluctuation behavior of the β-sheets and the T-loop in CDK6. Interaction networks of inhibitors with CDK6 were analyzed and the information reveals that 6ZV contributes more hydrogen binding interactions (HBIs) and hot interaction spots with CDK6. Our MM-GBSA calculations suggest that the binding ability of 6ZV to CDK6 is stronger than 6ZZ and 0RS. We anticipate that this work could provide useful information for further understanding of CDK6 function and developing new promising inhibitors targeting CDK6.

Topoisomerase II (Topo II) remains a validated target for anticancer therapy, with many clinically used agents acting via DNA intercalation and enzyme inhibition. However, their clinical use is limited by severe toxicity and resistance. In this study, we investigate aotaphenazine, a rare hydrophenazine derivative isolated from Streptomyces sp. IFM 11694 as a potential novel Topo II inhibitor with selective anticancer activity. Molecular docking and 400 ns molecular dynamics (MD) simulations were employed to evaluate aotaphenazine's binding mode within the DNA-Topo II complex (PDB: 3QX3). MM-GBSA calculations quantified interaction energetics, while ProLIF and PLIP analyses detailed the interaction patterns. Topo II inhibition was assessed via in vitro enzymatic assays. Cytotoxicity (MTT) assays were conducted against a panel of human cancer and normal cell lines. Flow cytometry was used to evaluate apoptosis and cell cycle progression in MDA-MB-231 cells. aotaphenazine demonstrated a docking binding energy of -19.12 kcal/mol and remained stably intercalated within the DNA groove during MD simulations. MM-GBSA analysis showed a total binding free energy of -29.81 kcal/mol, driven primarily by van der Waals forces. Interaction profiling identified consistent π-stacking with Cyt8 and Thy9, and strong binding contributions from Ade12 and Gua13. Enzymatic assays confirmed Topo II inhibition with an IC50 of 45.01 nM, comparable to doxorubicin (30.16 nM). In vitro cytotoxicity analysis revealed moderate activity across cancer cell lines (IC50 = 26.30-54.35 µM) and significantly reduced toxicity in normal WI-38 and WISH cells (IC50 = 69.86 µM and 84.72 µM, respectively). Flow cytometry showed that aotaphenazine induced early (20.98%) and late apoptosis (42.80%), along with S-phase cell cycle arrest (43.99%) and a marked reduction in the G2/M population in MDA-MB-231 cells. aotaphenazine exhibits a compelling combination of Topo II inhibition, DNA intercalation, and selective anticancer activity, supported by both computational modeling and biological validation. Its lower cytotoxicity toward normal cells and ability to induce apoptosis and cell cycle arrest suggest strong therapeutic potential. These findings establish aotaphenazine as a promising lead compound for the development of safer and more selective Topo II-targeting anticancer agents.

Alzheimer's disease (AD) is a neurodegenerative disorder with a gradual increase in severity. The underlying cause of the disease is the dysfunction of cholinergic neurotransmission affecting mainly the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Within the context of the present research, a new group of 3,5-disubstituted rhodanine derivatives containing tertiary amine groups has been prepared and their potency in the inhibition of AChE and BChE was assessed. Enzymatic assays demonstrated that compounds 6 and 11 exhibited exceptional inhibitory potency, with Ki values of 13.61 nM and 12.70 nM against AChE, and 10.44 nM and 25.11 nM against BChE, respectively, surpassing the reference inhibitors tacrine (145.21 nM for AChE and 169.54 nM for BChE) and donepezil (67.41 nM for AChE and 62.44 nM for BChE). Cytotoxicity studies confirmed minimal toxicity in human umbilical vein endothelial cells (HUVEC) at concentrations several times higher than the effective inhibitory doses (IC50 = 79.13 µM for 6 and 69.14 µM for 11). The results from molecular docking and MM-GBSA calculations supported this presumption by foretelling strong binding affinities, where compound 11 was the one to show a free energy of −103.26 kcal mol−1 for AChE and compound 6 −86.75 kcal mol−1 for BChE. Moreover, the 250 ns molecular dynamics simulations gave a confirmation of the structural stability and the prolonged existence of the key interactions in the enzyme active sites during the entire time. The findings of this research emphasize compounds 6 and 11 as potential candidates for the creation of strong cholinesterase inhibitors for the treatment of Alzheimer's disease, thus encouraging additional studies.

Quercetin, a naturally occurring flavonoid found in plants, has gained attention as a powerful quorum sensing (QS) inhibitor. However, the exact mechanism of its inhibitory effects is not yet fully understood. The Pseudomonas quinolone signal PQS has been demonstrated to trigger the formation of outer-membrane vesicles (OMVs) in Gram-negative bacteria, including Pseudomonas aeruginosa. Various other bacterial species have also responded to PQS, suggesting a shared biophysical mechanism. This study investigated the quorum-sensing inhibitory properties of Quercetin by assessing its binding affinity to the active site of PqsE (PDB: 2Q0J) using molecular docking, molecular dynamics simulations, and MM-GBSA assay. The results of molecular docking envisaged that the compound interacts with the target protein PqsE, exhibiting a binding energy value of (-7.46 kcal/mol; IC=3.39 µM). MD simulation over a time scale of 100 ns corroborated the interaction results obtained from molecular docking between Quercetin and the PqsE protein. In addition, MM-GBSA calculations confirmed that the compound Quercetin has high binding energies of -19.532 ± 16.048 Kcal/mol against PqsE protein. The strong binding affinity of the flavonoid quercetin, as demonstrated by in silico inhibition experiments, indicates its potential as a quorum-sensing inhibitor and its promise as a synergistic component in non-antibiotic therapeutic options for treating infections. Our findings reveal the molecular interactions involved in inhibiting the PqsE protein, resulting in blocking bacterial outer membrane vesicles. This sheds light on the essential aspects of the biophysical process underlying the antibacterial effects induced by Quercetin by inhibiting quorum sensing.

The use of the concept of privileged structures significantly accelerates the search for new leads and their optimization. 6-(methylsulfonyl)-8-(4-methyl-4H-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane 1 has been identified as a lead, with MICs of 0.0124-0.0441 μg/mL against MTb multiresistant strains. Several series of structural analogues have been synthesized, including variations in the periphery and simplifications of their scaffolds. All synthesized compounds were tested against the MTb H37Rv strain and ESKAPE panel of pathogens using serial broth dilutions. However, an attempt to optimize structure of 1 did not lead to the development of more active compounds which can work against MTb, but to substances with high activity against S. aureus. Induced-fit docking and MM-GBSA calculations determined a change in the likely biotarget from deazaflavin-dependent nitroreductase to azoreductases. The privileged nature of the scaffold was demonstrated by the detection of a different type of activity.

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from -9.6 to -7.6 and MM-GBSA scores ranging from -50.8 to -32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores.

Abstract Dengue fever, a viral disease transmitted by mosquitoes, presents a major public health risk in tropical and subtropical regions globally. Currently, there is no treatment to fight against this disease. The dengue virus 2 (DENV2) NS2B‐NS3 protease is critical for viral replication, making it a promising target for drug discovery. This study aims to identify potential inhibitors against the DENV2 NS2B‐NS3 protease using in silico methods, including molecular docking, ADMET analysis, molecular dynamics simulations, MMGBSA, and DFT calculations. We screened 1138 phytochemicals from the NuBBE database against the NS2B‐NS3 protease (PDB ID: 2FOM) and compared their binding affinities to policresulen, reported as DENV2 NS2B‐NS3 protease inhibitor. Four novel phytochemicals: 3′,4′‐methylenedioxy‐7,8‐(2″,2″‐dimethylpyrano)‐flavone; limonianin; gnetin‐B; and 5,4′‐dihydroxy‐3′,5′‐dimethoxy‐6,7‐(2″,2″‐dimethylpyran)flavonen revealed binding affinities of −8.7, −8.0, −7.8, and −7.8 kcal/mol, respectively, surpassing the reference compound's affinity of −7.0 kcal. Additionally, MD simulations over 100 ns confirmed the stability of these compounds bound with the target protein. Moreover, ADMET analysis demonstrated favorable pharmacokinetic and toxicity profiles, whereas MMGBSA and DFT calculations supported their binding consistency and reactivity. In conclusion, this study discovered promising novel phytochemicals against DENV2 NS2B‐NS3 protease, which could serve as potential leads for developing effective antiviral therapies for the treatment of dengue fever.

Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively. We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β. Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies. Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.

Identification of potential inhibitors for MAP4K4 in glaucoma using meta-dynamics-based dissociation free energy calculation

Rational design of some 1,3,4 trisubstituted pyrazole-thiazole derivatives to serve as MtInhA inhibitors using QSAR, ADMET, molecular docking, MM-GBSA, and molecular dynamics simulations approach

Breast cancer remains a major health threat throughout the world specifically in women above 30 years of age however, it is rarely known to affect men as well. It is characterized by the abnormal division of cells in the breast tissue resulting in the development of breast malignancies. Various risk factors contributing to breast cancer include age, family history, genetic mutations (chiefly in BRCA1 and BRCA2 genes) along with hormonal imbalances (oestrogen, progesterone, HER2). Early detection which can be obtained through frequent rounds of self-examination, mammographic scanning, and clinical assessment plays a crucial role in the prevention of the disease. In addition, appropriate diagnosis assists in better therapeutic responses. This study highlights the considerable health risks associated with the conventional treatment procedures which arise and increased demand of advanced, secure, and risk-free treatment alternatives. Oncolytic viruses are potentially apparent for the aim of improving cancer therapeutics with reduced side effects. These viruses act as the fundamental therapeutic agent themselves that selectively target and kill malignant cells without harm to healthy tissues. The key objective of the research is to provide evidence that Human Adenovirus 52 is a potent oncolytic virus and to highlight its capacity to target and eliminate cancer cells with precision while causing the least amount of harm to healthy tissues. Validating the in-silico method entails evaluating the precision and dependability of the computational modelling by contrasting the in-silico predictions with the findings from the experiments rank as the secondary objective. The workflow of this research utilized in-silico computational drug designing approaches including retrieval of tertiary structures of both the target Breast Cancer Type 1 Susceptibility Protein (BRCA1) and the viral Human Adenovirus 52 protein, their validation generating Ramachandran Plots determining favoured amino acid residue angles and prediction of their active residues. Furthermore, the study focused on the molecular dynamics docking of proteins, interpretation of molecular interactions between the docked complex, as well as the assessment of the molecular dynamic simulations (MD) in addition to their MMGBSA binding energy calculations. A successful docking between BRCA1 and Adenovirus protein provided a significant score of 329.2 +/- 24.3, furthermore, MD simulations showed a high RMSD peak at 2.8 Å, RMSF were maximum at 3.5 Å with highest protein–protein interaction, the radius of gyration was stable throughout the simulation representing elastic stability along with a high energy interaction value of - 7882 kCal/mol. Moreover, the MMGBSA calculation results showed a notable release of binding free energy of - 68.96 kCal/mol demonstrating effective bond formation between the docked complex. These findings propose the effectiveness of Human Adenovirus 52 to treat cancer. The selected oncolytic Human Adenovirus 52 is a potential candidate for the target specific treatment of breast cancer through virotherapy. This computer-aided drug discovery presents significant potential in targeting cancer cells and would assist in the development of potent drug reagents for the cancer therapy.

Phosphodiesterase 4B is an important enzyme belonging to the phosphodiesterase family, playing a role in regulating the levels of cyclic AMP in cells. Phosphodiesterase 4B degrades cyclic AMP, a crucial signaling molecule involved in numerous biological processes, including inflammation regulation. Recently, the search for potential inhibitors with fewer side effects and high biological activity in valuable medicinal plants has drawn the attention of current scientists. Various in silico methods have been applied to reduce costs and time for experimental studies. In this study, an in silico screening involving a set of 131 natural compounds sourced from Prinsepia utilis species was conducted. These compounds were docked into the active site of the phosphodiesterase 4B protein. As a result, 10 compounds exhibited the most potential inhibitory activity against phosphodiesterase 4B, including 2α- O-trans- p-coumaroyl-3 β,19 α-dihydroxy-urs-12-en-28-oic acid, 2 α- O-cis- p-coumaroyl-3 β,19 α-dihydroxy-urs-12-en-28-oic acid, cyanidin-3- O-rutinoside, delphinidin-3- O-rutinoside, peonidin-3- O-rutinoside, rutin, isorhamnetin-3- O-rutinoside, kaempferol 3- O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside-7- O- β-D-glucopyranoside, kaempferol 3- O- α-L-rhamnopyranosyl-(1→6) [ α-L-rhamnopyranosyl-(1→2)]- β-D-glucopyranoside, quercetin 3- O-α-L-rhamnopyranosyl-(1→6)- β-D-glucopyranoside were identified through molecular docking simulations. Subsequently, molecular dynamics simulations were performed on these complexes, revealing significant findings regarding their stability. Furthermore, MM–GBSA calculations indicated that the potential compounds had stronger binding free energies than the reference inhibitor. Finally, the selected compounds were subjected to toxicity prediction, showing noteworthy results with large LD50 values and safe toxicity levels. Therefore, these compounds could be potential candidates for further experimental studies as phosphodiesterase 4B inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been considered as global public health security threats. Due to its rapid spread, high mortality rate and unavailability of treatment, we need to find a potent drug against SARS-CoV-2. Natural products are useful agents for the discovery of new potential drugs to combat coronavirus. Artemisia campestris, an aromatic plant widely used in traditional medicine, particularly in southern region of Algeria, is recognized for its essential oils and phenolics compounds possessing a wide range of biological activities. This study selected sixty-nine compounds from this plant to determine their binding interactions with the SARS-CoV-2 main protease (Mpro) and receptor-binding domain of the spike (S-RBD) protein, by using computational methods. Rutin, isoquercetin, and quercetin-3-O-glucuronide were shown to be the most potent inhibitors for Mpro and S-RBD with docking scores and Ki values ranging from -16.06 to -10.67 Kcal/mol and 0.005 to 30.01 nM, respectively. Evaluation of ADMET pharmacokinetic properties and the drug likeness in silico revealed that only 3,5-dicaffeoylquinic acid, 3–4–5-tricaffeoylquinic acid, isorhamnetin-3-O-glucoside, and rubescensin A could be more effective drugs against COVID-19. Molecular dynamics (MD) simulations (100 ns) and MM-GBSA calculations confirmed the stability of ligand-protein complexes via hydrogen bonding interactions with crucial residues. The analysis of structural parameters (RMSD, RMSF, H-bonds, Rg, and SASA) indicates that 3,4,5-tricaffeoylquinic acid and rubescensin A compounds have good stability and significant binding affinity with the Mpro and S-RBD protein. Taken together, our findings confirm that Artemisia campestris as a plausible source of anti-SARS-COV-2 phytochemicals and suggest that may play important role in this activity.