Favorable Docking Scores Research Articles

Repurposed pharmacotherapy: targeting cathepsin L with repurposed drugs in virtual screening.

Proteolytic enzymes are closely associated with cancer and are important in different phases, including tumor growth, angiogenesis, and metastasis. Despite efforts to target matrix metalloproteases (MMPs), clinical trials have often resulted in various side effects such as musculoskeletal pain, joint stiffness, and tendinitis, making them less optimal for chronic cancer treatment. Thus, there is a need for the identification of other protease targets that would provide different approaches towards the management of cancer. Of these targets, Cathepsin L (CatL) is a lysosomal cysteine protease that has been identified as a therapeutic target that is implicated in cancer development and metastasis. In this study, we performed an integrated approach of virtual screening and molecular dynamics (MD) simulations to identify the potential inhibitors of CatL from a library of drugs that have been used for different treatments. Towards this goal, we performed virtual screening of the DrugBank database and found two repurposed drugs, Irinotecan and Nilotinib, against CatL based on their docking profiles, favorable docking scores, and specific interaction with the CatL binding pocket. MD simulations of the Irinotecan and Nilotinib bound structures with CatL were carried out, and the analysis showed that both these compounds could function as CatL inhibitors as the protein-ligand interactions were stable for 300 ns. This study highlights the robustness of these drugs bound to CatL and indicates that they could be repurposed for the treatment of cancer. These findings endorse the use of computer-based approaches for the identification of new inhibitors, and the present study will be a useful resource for future experimental research towards the targeting of CatL in cancer therapeutics.

MMV 1804559 is a potential antistaphylococcal and antibiofilm agent targeting the clfA gene of Staphylococcus aureus.

Staphylococcus aureus, a high-priority pathogen proclaimed to cause infections ranging from mild to life-threatening, presents significant challenges in treatment. New therapies can be developed quicker using open drug discovery platforms offering a distinct approach to expedite the development of innovative antibacterial and anti-biofilm therapeutics. This study set out to address these issues by finding new uses for current medications to find compounds that are effective against S. aureus. In this study, we screened the global priority health box, launched by Medicines for Malaria Ventures containing 240 compounds, for their effectiveness against S. aureus. MMV1795508, MMV1542799, MMV027331, MMV1593278, and MMV1804559 showed potential antibacterial activity at 10µM concentration. These compounds underwent further evaluation for their ability to clear intracellular bacteria, disrupt biofilm formation and eradicate existing biofilms. MMV1804559 demonstrated strong efficacy across all tested parameters, achieving 94% inhibition of intracellular bacteria, 79.19% disruption of biofilm cells, and 66.18% inhibition of biofilm formation. Scanning electron microscopy revealed notable membrane perforations and blebbing in MMV1804559-treated cells, indicating its impact on bacterial membranes. Gene expression analysis of cells treated with MMV1804559 showed downregulation of clfA and clfB genes, critical for biofilm formation. Additionally, docking studies confirmed the binding affinity of MMV1804559 with clfA, supported by favorable docking scores, MM/GBSA binding energy, and increased hydrogen bond interactions in the binding pocket, suggesting clfA as a target for MMV1804559. MMV1804559 could serve as a potential therapy for S. aureus by targeting biofilm development and cell adhesion processes.

In vivo and in silico insights into the antidiabetic efficacy of EVOO and hydroxytyrosol in a rat model

Extra virgin olive oil (EVOO) has a putative antidiabetic activity mostly attributed to its polyphenol Hydroxytyrosol. In this study, we explored the antidiabetic effects of EVOO and Hydroxytyrosol on an in vivo T2D-simulated rat model as well as in in silico study. Wistar rats were divided into four groups. The first group served as a normal control (NC), while type 2 diabetes (T2D) was induced in the remaining groups using a high-fat diet (HFD) for 12 weeks followed by a single dose of streptozotocin (STZ, 30 mg/kg). One diabetic group remained untreated (DC), while the other two groups received an 8-week treatment with either EVOO (90 g/kg of the diet) (DO) or Hydroxytyrosol (17.3 mg/kg of the diet) (DH). The DC group exhibited hallmark features of established T2D, including elevated fasting blood glucose levels, impaired glucose tolerance, increased HOMA-IR, widespread downregulation of insulin receptor expression, heightened oxidative stress, and impaired β-cell function. In contrast, treatments with EVOO and Hydroxytyrosol elicited an antidiabetic response, characterized by improved glucose tolerance, as indicated by accelerated blood glucose clearance. Systematic analysis revealed the underlying antidiabetic mechanisms: both treatments enhanced insulin receptor expression in the liver and skeletal muscles, increased adiponectin levels, and mitigated oxidative stress. Moreover, while EVOO reduced intramyocellular lipids, Hydroxytyrosol restored adipose tissue insulin sensitivity and enhanced β-cell survival. Molecular docking and dynamics confirm Hydroxytyrosol's high affinity binding to PGC-1α, IRE-1α, and PPAR-γ, particularly IRE-1α, highlighting its potential to modulate diabetic signaling pathways. Collectively, these mechanisms highlight the putative antidiabetic role of EVOO and Hydroxytyrosol. Moreover, the favorable docking scores of Hydroxytyrosol with PGC-1α, IRE-1α, and PPAR-γ support the antidiabetic potential and offer promising avenues for further research and the development of novel antidiabetic therapies.

Convenient Synthesis, Characterizations and Biological Evolution of Novel 1‐Phenyl‐N’‐(3‐phenylacryloyl)cyclopropane carbohydrazide Derivatives

AbstractCancer is a longstanding worldwide issue, current chemotherapeutic treatments have limited effectiveness and high toxicity. An extensive investigation has revealed a significant potential link between ITK and the development of cancer. Hence, it is recommended to prioritize investigating ITK to develop and produce novel inhibitors for treating diseases associated with T cells. In our study, we have designed and synthesized two new series of compounds, which consist of cinnamic acid, carbohydrazide, and cyclopropanamide groups in a single compound. We have developed a facile method to synthesize 20 new derivatives of two series of innovative 1‐phenyl‐N’‐(3‐phenylacryloyl)cyclopropane carbohydrazide derivatives with good yields and purity. The Synthesized derivatives are conformed by analytical techniques (FT‐IR, 1H NMR, 13C NMR, elemental analysis) and their biological evaluation data is provided. The synthesized compounds displayed favorable docking scores in comparison to the ITK inhibitor, Ibrutinib. The in vitro cancer investigation shows that these compounds have good IC50 values, causing cytotoxicity against malignant cell lines.

Evaluation of Bioactive Compounds in Tetrapleura tetraptera (Uyayak) and Its Activity Against Dihydropteroate Synthase (1AJ2) of E. coli: In-Sight from ADMET Profiling and Molecular Docking

Background: The prevalence of multi-drug-resistant E. coli isolates is on the increase around the world. This study was designed to evaluate the antimicrobial activity of Tetrapleura tetraptera (Uyayak) fruit bioactive compounds against E. coli using an in silico approach. Methods: Gas chromatography coupled to mass spectrophotometry (GC-MS) was used to identify the bioactive compounds in our sample T. tetraptera. The resulting bioactive compounds from GC-MS were converted into canonical strings and used for target and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties predictions using the pkCSM and SWISSADME tools, respectively. Bioactive compounds that met Lipinski's rule of five (ROF) were docked against the dihydropteroate synthase of E. coli using the AutoDock Vina tool, and the resulting interactions were visualized in 2-D using Biovia Discovery Studio 21. Results: The GC-MS analysis returned a total of twenty-eight (28) bioactive compounds, out of which 13 did not violate Lipinski's ROF. ADMET analysis of the screened bioactive compounds showed better absorption (intestinal and water solubility) and toxicity (AMES and hepatoxicity) profiles than trimethoprim, the control drug. Molecular docking gave docking scores that ranged from −4.0 to −5.3 kcal/mol for the bioactive compounds while that of trimethoprim was −6.5 kcal/mol. Target prediction showed that all the bioactive compounds are capable of reaching various targets, with the nuclear receptor being the most abundant target. Conclusion: The bioactive compounds of T. tetraptera fruits examined showed favorable docking scores and pharmacokinetics, suggesting the need for further studies to validate their potential as antimetabolites.

Expanded Gene Regulatory Network Reveals Potential Light-Responsive Transcription Factors and Target Genes in Cordyceps militaris.

Cordyceps militaris, a fungus widely used in traditional Chinese medicine and pharmacology, is recognized for its abundant bioactive compounds, including cordycepin and carotenoids. The growth, development, and metabolite production in various fungi are influenced by the complex interactions between regulatory cascades and light-signaling pathways. However, the mechanisms of gene regulation in response to light exposure in C. militaris remain largely unexplored. This study aimed to identify light-responsive genes and potential transcription factors (TFs) in C. militaris through an integrative transcriptome analysis. To achieve this, we reconstructed an expanded gene regulatory network (eGRN) comprising 507 TFs and 8662 regulated genes using both interolog-based and homolog-based methods to build the protein-protein interaction network. Aspergillus nidulans and Neurospora crassa were chosen as templates due to their relevance as fungal models and the extensive study of their light-responsive mechanisms. By utilizing the eGRN as a framework for comparing transcriptomic responses between light-exposure and dark conditions, we identified five key TFs-homeobox TF (CCM_07504), FlbC (CCM_04849), FlbB (CCM_01128), C6 zinc finger TF (CCM_05172), and mcrA (CCM_06477)-along with ten regulated genes within the light-responsive subnetwork. These TFs and regulated genes are likely crucial for the growth, development, and secondary metabolite production in C. militaris. Moreover, molecular docking analysis revealed that two novel TFs, CCM_05727 and CCM_06992, exhibit strong binding affinities and favorable docking scores with the primary light-responsive protein CmWC-1, suggesting their potential roles in light signaling pathways. This information provides an important functional interactive network for future studies on global transcriptional regulation in C. militaris and related fungi.

The Inhibiting Effect of GB-2, (+)-Catechin, Theaflavin, and Theaflavin 3-Gallate on Interaction between ACE2 and SARS-CoV-2 EG.5.1 and HV.1 Variants.

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, continues to pose significant global health challenges. The results demonstrated that GB-2 at 200 μg/mL effectively increased the population of 293T-ACE2 cells with low RBD binding for both SARS-CoV-2 Omicron EG.5.1 and HV.1 variants by dual-color flow cytometry, indicating its ability to inhibit virus attachment. Further investigation revealed that (+)-catechin at 25 and 50 μg/mL did not significantly alter the ACE2-RBD interaction for the EG.5.1 variant. In contrast, theaflavin showed inhibitory effects at both 25 and 50 μg/mL for EG.5.1, while only the higher concentration was effective for HV.1. Notably, theaflavin 3-gallate exhibited a potent inhibition of ACE2-RBD binding for both variants at both concentrations tested. Molecular docking studies provided insight into the binding mechanisms of theaflavin and theaflavin 3-gallate with the RBD of EG.5.1 and HV.1 variants. Both compounds showed favorable docking scores, with theaflavin 3-gallate demonstrating slightly lower scores (-8 kcal/mol) compared to theaflavin (-7 kcal/mol) for both variants. These results suggest stable interactions between the compounds and key residues in the RBD, potentially explaining their inhibitory effects on virus attachment. In conclusion, GB-2, theaflavin, and theaflavin 3-gallate demonstrate significant potential as inhibitors of the ACE2-RBD interaction in Omicron variants, highlighting their therapeutic promise against COVID-19. However, these findings are primarily based on computational and in vitro studies, necessitating further in vivo research and clinical trials to confirm their efficacy and safety in humans.

GSK-3β and Non-Small Cell Lung Cancer: A Review of Its Role in Disease Mechanisms and Treatment Strategies

Introduction Recent molecular docking studies have identified potential inhibitors targeting GSK-3β, offering promising avenues for therapeutic intervention. These inhibitors could potentially disrupt the oncogenic signaling pathways mediated by GSK-3β, thereby halting or reversing tumor progression. This literature review seeks to deliver a thorough examination of the current knowledge regarding GSK-3β influence on NSCLC. Methods The author carried out an extensive literature review utilizing various electronic databases such as PubMed, Scopus, and Europe PMC. The search keywords included "GSK-3β," "glycogen synthase kinase-3 beta," "non-small cell lung cancer," "NSCLC," "prognosis," "apoptosis," "cell proliferation," "autophagy," "radiosensitivity," "tumor differentiation," and "molecular docking." The findings from the included studies were integrated into a narrative review, emphasizing GSK-3β role in NSCLC pathogenesis, its potential as a therapeutic target, and its utility as a prognostic biomarker. Results GSK-3β is a multifunctional serine/threonine kinase involved in various cellular processes, including proliferation, differentiation, motility, and survival. Its expression is associated with NSCLC differentiation, with GSK-3β-negative tumors showing better prognosis. Preclinical studies have identified potential GSK-3β inhibitors with favorable docking scores and ADME profiles for NSCLC treatment. However, targeting GSK-3β for NSCLC treatment faces several significant challenges. One major issue is the broad role of GSK-3β in various cellular processes, including metabolism and cell survival, which increases the risk of off-target effects and toxicity. Conclusions GSK-3β has emerged as a critical biomarker in NSCLC, exerting a significant impact on disease progression, treatment response, and prognosis.

Structural insights into Furin enzyme inhibition to block SARS-CoV-2 spike protein cleavage: an in-silico approach.

This study investigates the binding affinity and interactions of the Furin enzyme with two inhibitors, Naphthofluorescein and decanoyl-RVKR-chloromethylketone (CMK), using molecular docking and molecular dynamics (MD) simulations. Molecular docking results showed binding affinities of -9.18kcal/mol for CMK and -5.39kcal/mol for Naphthofluorescein. To further understand the stability and conformational changes of these complexes, MD simulations were performed. Despite CMK's favorable docking score, MD simulations revealed that its binding interactions at the Furin-active site were unstable, with significant changes observed during the simulation. In contrast, Naphthofluorescein maintained strong and stable interactions throughout the MD simulation, as confirmed by RMSD and RMSF analyses. The binding-free-energy analysis also supported the stability of Naphthofluorescein. These findings indicate that Naphthofluorescein exhibits greater stability and binding affinity as a Furin inhibitor compared to CMK. The results of this in-silico study suggest that Naphthofluorescein, along with CMK, holds the potential for repurposing as a treatment for COVID-19, subject to further validation through clinical studies.

Glucoimines incorporating classical and non-classical carbonic anhydrase pharmacophores: Design, synthesis, conformational analysis, biological evaluation, and docking simulations

In this report, a series of glucoimines has been prepared by reaction of d-glucosamine and aromatic aldehydes incorporating classical and non-classical carbonic anhydrase pharmacophores. The conformational behavior of veratrole glucoimine was studied in solution and in crystalline form, by NMR and X-ray diffraction analysis, which revealed that pyranose ring adopted a 4C1 conformation. All glucoimines were tested against four isozymes of carbonic anhydrase: hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (tumor-associated isozymes). In this study, per-O-acetylated and deprotected sulfonamide were identified as potent inhibitors of tumor-associated carbonic anhydrase isoforms. Molecular docking simulation was performed inside the active site of hCA II to evaluate the binding modes of veratrole and sulfonamide glucoimines. The last ones demonstrated the most favorable docking scores, indicating strong binding affinity towards hCAII in correlation with experimental inhibition activities. Interestingly, interaction analyses revealed distinct binding modes for ligand-hCAII complexes primarily due to the sulfonamide group.

Developing a Semi-Supervised Approach Using a PU-Learning-Based Data Augmentation Strategy for Multitarget Drug Discovery.

Multifactorial diseases demand therapeutics that can modulate multiple targets for enhanced safety and efficacy, yet the clinical approval of multitarget drugs remains rare. The integration of machine learning (ML) and deep learning (DL) in drug discovery has revolutionized virtual screening. This study investigates the synergy between ML/DL methodologies, molecular representations, and data augmentation strategies. Notably, we found that SVM can match or even surpass the performance of state-of-the-art DL methods. However, conventional data augmentation often involves a trade-off between the true positive rate and false positive rate. To address this, we introduce Negative-Augmented PU-bagging (NAPU-bagging) SVM, a novel semi-supervised learning framework. By leveraging ensemble SVM classifiers trained on resampled bags containing positive, negative, and unlabeled data, our approach is capable of managing false positive rates while maintaining high recall rates. We applied this method to the identification of multitarget-directed ligands (MTDLs), where high recall rates are critical for compiling a list of interaction candidate compounds. Case studies demonstrate that NAPU-bagging SVM can identify structurally novel MTDL hits for ALK-EGFR with favorable docking scores and binding modes, as well as pan-agonists for dopamine receptors. The NAPU-bagging SVM methodology should serve as a promising avenue to virtual screening, especially for the discovery of MTDLs.

Investigation of Some Metabolic Enzyme Inhibition Properties of Novel Chalcone‐Cu Complexes

AbstractFourteen novel Chalcone‐Cu complexes were effectively synthesized in this work. The newly synthesized Chalcone‐Cu complexes were assessed for their effects on human carbonic anhydrase isoenzymes I and II, acetylcholinesterase enzymes, and antioxidant activity. The intricate compounds exhibited Ki values ranging from 41.65–190.42 nM against hCA I, 15.79–259.07 nM against hCA II, and 14.36–175.73 nM against AChE enzymes. These complexes demonstrated potent inhibitory profiles against the specified metabolic enzymes, surpassing the inhibitory effects of acetazolamide (for hCA I and II) and tacrine (for AChE). The antioxidant properties of the compounds were assessed using DPPH and ABTS radical scavenging assays, revealing that the complexes had moderate to high efficacy in neutralizing free radicals. All complexes underwent molecular docking experiments. Compounds 14, 22, and 23 yielded the highest docking scores. Compound 14 demonstrated a docking score of −6.414 kcal/mol against hCAI, whereas compound 23 attained a docking score of −6.697 kcal/mol against hCA II. Compound 22 exhibited the most favorable docking score of −9.645 kcal/mol against AChE. The acquired results have the potential to help towards the development of new drugs containing Cu complex structures for the treatment of prevalent ailments such as glaucoma and Alzheimer's diseases.

Design, synthesis and biological Evaluation of novel chromones having 3,4-dihydropyrimidin-2(1H)-one core at C-8 in combination with triazoles: New α-glucosidase inhibitors and anti-bacterial agents

The Biginelli reaction synthesizes dihydropyrimidones through a multi-component reaction. A β-ketoester, aldehyde, and urea or thiourea react in the presence of an acid catalyst to form these dihydropyrimidones. 3,4-Dihydropyrimidin-2(1H)-One/Chromone/Triazole hybrids (9a-9l) were synthesized by multiple steps including one pot Biginelli multicomponent reaction depicted in the scheme. An efficient method for the Biginelli reaction of Chromone aldehyde, acetoacetate esters, and urea employed in the presence of ferric chloride is described. In the end, we have successfully synthesized twelve derivatives of 3,4-Dihydropyrimidin-2(1H)-One/Chromone/Triazole hybrids and subjected them to testing for Antibacterial activity and α-glucosidase inhibition activity. Among these derivatives, compound 9g (IC50 = 142.92 nmol) and 9e (144.49 nmol) exhibited significant inhibitory activity in comparison to the positive control acarbose (IC50 = 350.91 nmol). Compound 9g demonstrated the most significant suppression against Escherichia coli and Bacillus cereus, with zone diameters of 8.8 ± 1.35 mm and 9.1 ± 0.23 mm, respectively. Compound 9b displayed a clear area where bacterial growth was inhibited, measuring 7.5 ± 1.25 mm against Klebsiella pneumonia. Compound 9k exhibited a zone of inhibition measuring 8 ± 1.2 mm in radius against Staphylococcus epidermidis. The docking results for the synthesized compounds indicate that compound 9b exhibited the most favorable docking score of −10 kcal/mol, whereas compound 9a had the second-best docking score of −8.7 kcal/mol. Molecular docking was utilized to examine the interactions between the title compounds and α-glucosidase, in order to provide valuable insights. The data obtained revealed significant interactions that contribute to the inhibitory effects of the drugs against α-glucosidase. These compounds exhibit significant potential as attractive initial candidates for the development of new α-glucosidase inhibitors.

Computational design and validation of siRNA molecules to silence oncogenic CTNNB1 mRNA as a potential therapeutic strategy against hepatitis B/C virus-associated hepatocellular carcinoma

The majority of hepatocellular carcinoma cases are caused by infection with hepatitis B (HBV) or C (HCV) viruses. CTNNB1 is the most mutated oncogene in HBV- and HCV-associated tumors. CTNNB1 mutations can lead to β-catenin accumulation, resulting in tumor progression. Small interfering RNAs (siRNAs) can be used to silence CTNNB1 mRNA. After prediction and evaluation, four siRNAs were found to have the highest silencing potential. All four siRNAs had an acceptable GC content, no palindromic sequences, no off-targets, were thermostable, and had accessible target sites. Molecular docking of the siRNAs to Argonaute 2 demonstrated favorable docking scores within the binding pocket for three siRNAs. Molecular dynamics simulations and binding energy calculations demonstrated that the siRNAs steadily remained in the binding pocket. In this study, three siRNAs were successfully designed to silence oncogenic CTNNB1 mRNA as a therapeutic strategy against hepatocellular carcinoma and warrant further in vitro and in vivo validation.

Epigallocatechin gallate and curcumin inhibit Bcl-2: a pharmacophore and docking based approach against cancer

The protein Bcl-2, well-known for its anti-apoptotic properties, has been implicated in cancer pathogenesis. Identifying the primary gene responsible for promoting improved cell survival and development has provided compelling evidence for preventing cellular death in the progression of malignancies. Numerous research studies have provided evidence that the abundance of Bcl-2 is higher in malignant cells, suggesting that suppressing Bcl-2 expression could be a viable therapeutic approach for cancer treatment. In this study, we acquired a compound collection using a database that includes constituents from Traditional Chinese Medicine (TCM). Initially, we established a pharmacophore model and utilized it to search the TCM database for potential compounds. Compounds with a fitness score exceeding 0.75 were selected for further analysis. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis identified six compounds with favorable therapeutic characteristics. The compounds that successfully passed the initial screening process based on the pharmacodynamic model were subjected to further evaluation. Extra-precision (XP) docking was employed to identify the compounds with the most favorable XP docking scores. Further analysis using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method to calculate the overall free binding energy. The binding energy between the prospective ligand molecule and the target protein Bcl-2 was assessed by a 100 ns molecular dynamics simulation for curcumin and Epigallocatechin gallate (EGCG). The findings of this investigation demonstrate the identification of a molecular structure that effectively inhibits the functionality of the Bcl-2 when bound to the ligand EGCG. Consequently, this finding presents a novel avenue for the development of pharmaceuticals capable of effectively addressing both inflammatory and tumorous conditions.

Integrated pharmacophore‐based screening and docking strategy for identifying type II inhibitors of VEGFR‐2 kinase

Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis represent indispensable methodologies in modern drug discovery, offering insights into ligand-receptor interactions and aiding in the rational design of potent therapeutic agents. This study presents a thorough investigation into the identification of novel inhibitors targeting VEGFR-2 kinase, a key regulator in angiogenesis and a promising target in oncology.Leveraging a dataset comprising 72 type-II inhibitors, a series of pharmacophore hypotheses were developed using a set of six active ligands. Subsequent evaluation led to the selection of top-performing hypotheses, ADDHRR_6 and ADDHRR_10, which demonstrated good predictive capabilities in atom-based 3D QSAR modeling.Virtual screening of the Maybridge database using these pharmacophore hypotheses resulted in the identification of potential hits, which were evaluated through molecular docking analyses. Ten compounds exhibited favorable docking scores and important interactions with key residues, such as Glu885, Glu917, Cys919, and Asp1046.Additionally, comprehensive absorption, distribution, metabolism, and excretion (ADME) analysis was performed and indicated that these compound had acceptable physicochemical properties. These findings highlight the utility of integrated pharmacophore-based screening and molecular docking approaches in the identification of novel type II VEGFR-2 kinase inhibitors.

Molecular Docking, Molecular Dynamics Simulation, and Analysis of EGFR-derived Peptides against the EGF

Background: The epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family known as ErbB. The EGFR signaling pathway is an important regulator of cell proliferation, differentiation, division, and survival, as well as cancer development in humans. Epidermal growth factor, betacellulin, amphiregulin, transforming growth factor and heparin-binding EGF-like growth factor are high-affinity ligands of EGFR. Objective: Tumor progression can be effectively prevented by inhibiting EGF/EGFR interactions. In this study, many anti-EGF peptides targeting EGFR binding regions were designed, modeled, and evaluated. After selecting the peptides with the highest binding energy to the EGF, the interactions between the candidate peptides and all of the key EGFR ligands were investigated. Methods: To identify an EGF-binding peptide capable of blocking EGFR-EGF interactions, large-scale peptide mutation screening was performed. Using the AntiCP server, several possible peptides with anticancer properties were identified. The ClusPro analysis was performed in order to analyze the interactions between EGF and all of the library peptides. A total of five peptides with favorable docking scores were identified. The stability of three peptides with the best docking scores in complex with EGF was verified, applying molecular dynamics simulation with the help of the GROMACS software package. Finally, the interaction of candidate peptides with transforming growth factor-alpha, heparin-binding EGF-like growth factor, and betacellulin was investigated using the ClusPro server. Results: After the screening of modeled peptides by the ClusPro server and GROMACS software, two anti-EGF peptides of Pep4 and Pep5 with 31 residues were developed. Then, we demonstrate that both of these peptides can bind to the other high-affinity ligands of EGFR and block TGFA/EGFR, HBEGF/EGFR, and BTC/EGFR interactions. Conclusion: The findings suggest novel insights for developing therapies based on peptides for inhibiting the EGF, TGFA, HBEGF, and BTC signaling cascade in cancer cells. Pep4 and Pep5 designed in this work, are recommended as potentially promising anticancer peptides for further experimental evaluation.

Exploring the Antibacterial Potential of Artemisia judaica Compounds Targeting the Hydrolase/Antibiotic Protein in Klebsiella pneumoniae: In Vitro and In Silico Investigations.

Carbapenem antibiotic resistance is an emerging medical concern. Bacteria that possess the Klebsiella pneumoniae carbapenemase (KPC) protein, an enzyme that catalyzes the degradation of carbapenem antibiotics, have exhibited remarkable resistance to traditional and even modern therapeutic approaches. This study aimed to identify potential natural drug candidates sourced from the leaves of Artemisia judaica (A. judaica). The phytoconstituents present in A. judaica dried leaves were extracted using ethanol 80%. A reasonable amount of the extract was used to identify these phytochemicals via gas chromatography/mass spectrometry (GC/MS). One hundred twenty-two bioactive compounds from A. judaica were identified and subjected to docking analysis against the target bacterial protein. Four compounds (PubChem CID: 6917974, 159099, 628694, and 482788) were selected based on favorable docking scores (-9, -7.8, -7.7, and -7.5 kcal/mol). This computational investigation highlights the potential of these four compounds as promising antibacterial candidates against the specific KPC protein. Additionally, in vitro antibacterial assays using A. judaica extracts were conducted. The minimum inhibitory concentration (MIC) against the bacterium K. pneumonia was 125 μg/mL. Well-disk diffusion tests exhibited inhibition zones ranging from 10.3 ± 0.5 mm to 17 ± 0.5 mm at different concentrations, and time-kill kinetics at 12 h indicated effective inhibition of bacterial growth by A. judaica leaf extracts. Our findings have revealed the pharmaceutical potential of Artemisia judaica as a natural source for drug candidates against carbapenem-resistant pathogens.

Identification of Phytochemical Inhibitors Targeting VEGFA and TGFBR2 of Cervical Cancer: Insights from Virtual Screening, ADMET and DFT Studies

AbstractThe vascular endothelial growth factor A (VEGFA) and Transforming Growth Factor Beta type II receptor (TGFBR2) serves as a promising candidate in the treatment of cervical cancer, playing a crucial role in angiogenesis and tumorigenesis. Its involvement in cervical cancer has been well documented. The pursuit of phytochemical inhibitors to counteract the cancer promoting effects of VEGFA and TGFBR2 has gained considerable momentum as very few drugs are available. In this study, we employed computational techniques to identify potential VEGFA and TGFBR2 inhibitors from 101 phytochemicals. The Spirosolane, Withaferin A & Silybin B for VEGFA and Ginkgetin, Hesperedin for TGFBR2 were identified as promising candidates as indicated by their favorable docking scores and robust energy profiles. Furthermore, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile indicating that Spirosolane and Ginkgetin exhibit favorable drug‐like properties and medicinal chemistry characteristics, suggesting their potential as novel drug candidates. The Density Functional Theory (DFT) studies revealed that these compounds exhibited the highest electrophilicity index for occupied molecular orbitals, basicity, and dipole moment, all contributing to their stability and strong binding affinity at the active site. To advance this line of research, additional experimental validation is warranted to facilitate the development of highly selective and effective VEGFA and TGFBR2 inhibitors.

Computational investigation of 2, 4-Di Tert Butyl Phenol as alpha amylase inhibitor isolated from Coccinia grandis (L.) Voigt using molecular docking, and ADMET parameters

IntroductionDiabetes Mellitus is the metabolic disorder most prevalent globally, accounting for a substantial morbidity rate. The conventional drugs available for the management of diabetes are either expensive or lack the required efficacy. The purpose of this research is to isolate and characterize an active phytoconstituent from Coccinia grandis and assess its anti-diabetic properties. Methods and materialsStems of Coccinia grandis are subjected to successive extraction and isolation. The isolated compound by column chromatography was characterized by FTIR (fourier-transform infrared), 1 H NMR (proton nuclear magnetic resonance), and Mass spectroscopy. The antidiabetic potential of the isolated compound was evaluated by in-vitro alpha-amylase inhibitory activity. Further, the compound was subjected to molecular docking studies to study its interaction with the human pancreatic alpha-amylase (Molegro Virtual Docker) as well to determine the pharmacokinetic and toxicity profile using computational techniques (OSIRIS property explorer, Swiss ADME, pkCSM, and PreADMET). ResultsThe characterization of the compound suggests the structure to be 2,4-ditertiary butyl phenol. The in-vitro alpha-amylase inhibitory study indicated a concentration-dependent inhibition and the IC50 (median lethal dose) value of the isolated compound was found to be 64.36 μg/ml. The docking study with the A chain of receptor 5EMY yielded a favorable docking score of −81.48 Kcal mol−1, suggesting that the compound binds to the receptor with high affinity through electrostatic, hydrophobic, and hydrogen bonds. Furthermore, the silico ADME analysis of the compound revealed improved metabolism, a skin permeability of −3.87 cm/s, gastrointestinal absorption of 95.48 %, and a total clearance of 0.984 log ml min−1 kg−1. In silico toxicity analysis also predicted cutaneous irritations but no carcinogenicity, mutagenicity, or hepatotoxicity. ConclusionThe data suggested that the isolated compound (2, 4-tertiary butyl phenol) has the potential to inhibit the alpha-amylase activity and possess optimal ADME properties as well as tolerable side effects.