In silico investigation combining ADMET prediction, periodic DFT calculations, molecular docking, and nanocarrier-based drug delivery analysis for leukemia drugs using a B₂N nanosheet

Crystal structure, stability, and electronic properties of hydrated metal sulfates MSO4(H2O)n (M=Ni, Mg; n=6, 7) and their mixed phases: A first principles study

1-Ethoxycarbonyl-beta-carboline inhibits the M2 polarization of tumor-associated macrophages: A study based on network pharmacology and molecular docking analyses

Aedes aegypti is the primary vector of dengue, a significant public health problem in many countries. Controlling of Ae. aegypti is the biggest challenge in the mosquito control programe, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission. To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1- phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis. All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects. Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC<50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM). The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programe.

A review of computational studies on the structures, bonding and reactivity of rhodium σ-alkane complexes in the solid state is presented. These complexes of the general form [(R2P(CH2)nPR2)Rh(alkane)][BArF4] (where ArF = 3,5-(CF3)2C6H3) are formed via solid/gas hydrogenation of alkene precursors, often in single-crystal-to-single-crystal (SC-SC) transformations. Molecular and periodic density functional theory (DFT) calculations complement experimental characterisation techniques (X-ray, solid-state NMR) to provide a detailed picture of the structure and bonding in these species. These σ-alkane complexes exhibit reactivity in the solid state, undergoing fluxional processes, and access different alkane binding modes that link to C-H activation and H/D exchange. The mechanisms of several of these processes have been defined using periodic DFT calculations which provide excellent quantitative agreement with the available experimental activation barriers. A comparison of computed results derived from periodic DFT calculations, where the full solid-state environment is taken into account, with simple model calculations using the isolated molecular cations highlights the importance of modelling the solid state to reproduce the structures of these alkane complexes. The solid-state environment can also have a significant impact on the computed reaction energetics.

Anti-malarial proguanil (1) and phenoxypropoxy biguanide derivatives (2–9) are prodrugs. Their efficacy is directly proportional to the quantity of active triazine metabolites produced from these prodrugs. Detailed molecular docking analyses for all nine drug candidates in the active site of CYP3A4, CYP2D6, and CYP2C19 were carried out under the influence of induced-fit effect of ligand during molecular dynamic simulations. We have developed a strategy based on docking pose clusters to quantify the production of active metabolites for this class of molecules. For all drugs, site of metabolism based clusters of docking poses were prepared in both phases of the molecular docking analyses and correlated with the percentage of metabolites generated in the pooled human liver microsomes study. The total numbers of docking poses representing active metabolite formation were found to be well correlated with the experimental results in post-induced fit docking analyses. This strategy was first validated using proguanil, PS-15 and JPC-2056. Further, this methodology was employed to correlate the theoretically predicted metabolite formation of 4–9 to the experimentally estimated values which further led to clues on isoenzyme specificity in producing the metabolites. Binding requirements of these leads in the active sites of CYPs were also explored in this study.

The COVID-19 pandemic began in 2019 as a result of the advent of a novel coronavirus, SARS-CoV-2. At present, there are a limited number of approved antiviral agents for the treatment of COVID-19. Remdesivir, Molnupiravir, and Paxlovid have been approved by the FDA to treat COVID-19 infections. Research has shown that the main protease enzyme (Mpro) of SARS-CoV-2 plays a crucial role in the enzymatic processing of viral polyproteins. This makes Mpro an interesting therapeutic target for combating infections caused by emerging coronaviruses. The pharmacological effects of pyrroles and their derivatives have a wide range of applications. In our study, we focused on synthesizing nine novel derivatives of 2-arylamino-dihydro-indeno[1,2-b] pyrrol-4(1H)-one, with a particular emphasis on their antiviral properties. Using in silico studies involving molecular docking and DFT analyses in the gas phase using the B3LYP/6-31++G(d,p) basis set, we studied these compounds with respect to their interactions with the Mpro of SARS-CoV-2. The results of the docking analysis revealed that the synthesized compounds exhibited favorable inhibitory effects. Notably, compound 5f demonstrated the highest effectiveness against the target protein. Furthermore, the pharmacokinetic and drug-like properties of the synthesized derivatives of 2-arylamino-dihydroindeno[1,2-b] pyrrol-4(1H)-one indicated their potential as promising candidates for further development as inhibitors targeting SARS-CoV-2. However, it is imperative to determine the in vitro efficacy of these compounds through comprehensive biochemical and structural analyses.

Identification of dietary compounds that interact with the circadian clock machinery: Molecular docking and structural similarity analysis

ABSTRACT‘Obesogens’ are chemical agents that improperly regulate the genes involved in glucose metabolism and adipocyte differentiation and promote lipid accumulation and adipogenesis. The human glucocorticoid receptor (hGR) is a steroid hormone triggered transcriptional factor and regulates target genes important in basal glucose homeostasis. Molecular docking analysis was performed in order to assess in-silico structure based toxic effects of high molecular weight phthalates dicyclohexyl phthalate (DCHP) and its monophthalate metabolite mono-cyclohexyl phthalate (MCHP). Molecular docking results show that the binding affinities of DCHP and MCHP lie in the comparable range (−7.87 kcal/mol and −6.24 kcal/mol) with Dexamethasone (−10.2 kcal/mol), a potent agonist for hGR. These two PAEs occupy the active site of hGR and interact with the key residues. Molecular simulation results infer that hGR-PAEs complexes were stable. Density functional theory (DFT) analysis indicates that HOMO and LUMO energy gap of DCHP (3.88 eV) and MCHP (3.39 eV) are comparable to DEX (4.69 eV). Binding free energy calculations of the DCHP-hGR and MCHP-hGR complexes were estimated by using Molecular Mechanic/Poisson-Boltzmann Surface Area (MMPBSA) method. Molecular Docking and simulation results emphasise that DCHP and MCHP can efficiently bind to hGR, which further leads to glucocorticoid-mediated adipogenesis in a synergistic manner.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal tumors worldwide, with limited effective treatments. Globally, the incidence of pancreatic cancer is expected to rise to 18.6 per 100,000 by 2050, with an average annual growth rate of 1.1%, implying that PDAC would represent a considerable public health burden. Identifying prognostic markers is critical for making therapy decisions and improving patient outcomes. In this study, the microarray gene expression data of PDAC were analyzed using artificial intelligence (AI) algorithms and molecular docking to identify the differentially expressed genes (DEGs) and drug repurposing. The GSE183795 dataset used in this study was obtained from the National Centre for Biotechnology Information. Further, the data were analyzed using GEO2R tools, and genes were selected based on logFC values>2. Then, these genes were ranked using AI algorithms such as support vector machine (SVM), logistic regression, random forest, extreme gradient boosting (XGB), and one-dimensional convolutional neural network to identify the DEGs. The performance of the models was evaluated using stratified 10-fold cross-validation and different classification metrics. A drug library was prepared using DepMap corresponding to the identified DEGs, and subsequently, molecular docking and pharmacokinetics analysis were performed. The result of the logFC>2 listed 107 upregulated genes in PDAC. It was observed that SVM and XGB show the average 10-fold accuracy, sensitivity, specificity, precision, and F-score of 79.25%, 78.37%, 78.37%, 79.33% and 78.35% respectively. Our results revealed that LIFR, BTG2, EPHX2, and PAK3 are within the top three and commonly ranked by AI models. Further, we identified three drugs, such as BI-2536, Ponatinib (AP-24534), and AZ-628, which show the best efficacy based on the binding energies by molecular docking analysis. The pharmacokinetics study strengthened our results that the identified drugs can be used as a therapeutic for PDAC as they obey Lipinski's rule. In conclusion, identified genes can act as prognostic markers, and drugs could be used as potential therapeutics for PDAC.

Azadirachta indica A. Juss. is a well-known medicinal plant that has been used traditionally to cure various ailments in every corner of the globe. There are many in vitro and in vivo experimental evidences in connection with the bioactivity of the extracts of this plant. Lung cancer is the deadliest form of cancer and contributes to the most cancer related deaths. The mode of action of anticancer components of this plant is still to be established explicitly. The objective of this study is to identify druggable targets of active constituents of A. indica A. Juss. for non-small cell lung cancer (NSCLC) using network pharmacology and validation of activity through molecular docking analysis. Targets of all the active phytochemicals from A. indica were predicted and genes related to NSCLC were retrieved. A protein-protein interaction (PPI) network of the overlapping genes were prepared. Various databases and servers were employed to analyse the disease pathway enrichment analysis of the clustered genes. Validation of the gene/protein activity was achieved by performing molecular docking, and ADMET profiling of selected phytocompounds was performed. Gene networking revealed three key target genes as EGFR, BRAF and PIK3CA against NSCLC by the active components of A. indica. Molecular docking and ADMET analysis further validated that desacetylnimbin, nimbandiol, nimbin, nimbinene, nimbolide, salannin and vepinin are the best suited anti- NSCLC among all the phytocompounds present in this plant. The present study has provided a better understanding of the pharmacological effects of active components from A. indica and its potential therapeutic effect on NSCLC.

Designing and developing small organic molecules for use as urease inhibitors is challenging due to the need for ecosystem sustainability and the requirement to prevent health risks related to the human stomach and urinary tract. Moreover, imaging analysis is widely utilized for tracking infections in intracellular and in vivo systems, which requires drug molecules with emissive potential, specifically in the low-energy region. This study comprises the synthesis of a Schiff base ligand and its selected transition metals to evaluate their UV/fluorescence properties, inhibitory activity against urease, and molecular docking. Screening of the symmetrical cage-like ligand and its metal complexes with various eco-friendly transition metals revealed significant urease inhibition potential. The IC50 value of the ligand for urease inhibition was 21.80 ± 1.88 µM, comparable to that of thiourea. Notably, upon coordination with transition metals, the ligand-nickel and ligand-copper complexes exhibited even greater potency than the reference compound, with IC50 values of 11.8 ± 1.14 and 9.31 ± 1.31 µM, respectively. The ligand-cobalt complex exhibited an enzyme inhibitory potential comparable with thiourea, while the zinc and iron complexes demonstrated the least activity, which might be due to weaker interactions with the investigated protein. Meanwhile, all the metal complexes demonstrated a pronounced optical response, which could be utilized for fluorescence-guided targeted drug delivery applications in the future. Molecular docking analysis and IC50 values from in vitro urease inhibition screening showed a trend of increasing activity from compounds 7d to 7c to 7b. Enzyme kinetics studies using the Lineweaver-Burk plot indicated mixed-type inhibition against 7c and non-competitive inhibition against 7d.

Inflammatory response plays important roles in both tumorigenesis and carcinogenesis. In this study, secondary metabolite compounds from Lactococcus lactis subsp. lactis (Lac3) were analyzed by LC-MS and the potential inhibition activity against the COX-2 receptor was screened through molecular docking and molecular dynamics (MD) analysis. Anti-inflammatory agents, mofezolac and ibuprofen, were used as positive control ligands. The result indicates a potential COX-2 inhibitor of 5-[(4-Amino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]-2- methylbenzenesulfonate, which has a hydrogen bond on the active site Tyr385 of COX-2 with affinity energy of –9.0 kcal/mol. Moreover, another candidate of COX-2 inhibitor, designated as 3-Indolepropionic acid binds hydrogen on the important residue Ser530 of COX-2, with an affinity energy of –6.9 kcal/mol. To confirm the binding specificity, molecular docking analysis was also performed against COX-1. The binding stability and flexibility were confirmed using MD simulations. In addition, the toxicity and solubility of the potential ligands were predicted according to Lipinski’s rules and BOILED-Egg modeling. The 5-[(4-Amino-6-morpholin-4-yl- 1,3,5-triazin-2-yl)amino]-2-methylbenzenesulfonate shows the propensity for passive absorption through the gastrointestinal tract, whereas 3-Indolepropionic acid shows a high probability of blood-brain barrier penetration. In conclusion, this study identified potential compounds through molecular docking analysis which can be developed as COX-2 inhibitors.

Background: The replication of monkeypox in the skin is critical to understanding its pathogenesis and spread. p37, a highly conserved 37 kDa peripheral membrane protein encoded by the F13L gene in Orthopoxvitidae is a validated target for anti-poxviral medication like tecovirimat, the first FDA-approved anti-poxviral drug that was approved in 2018. The detailed recognition mechanism of tecovirimat on p37 of monkeypox has not been fully clarified. As p37, HSV-1 gD and HSV-2 gD proteins of HSV are viral envelope glycoproteins identified as ligands for the human nectin-1 as a functional receptor of permissive cells. The use of non-damaging light for microbial inactivation (MI) has been documented for different virus like HSV, where photosensitizers (PSs) are used as lightresponsive agents which could generate antiviral responses primarily by oxidation. In addition, some PSs could elicit antiviral responses in a light-independent way by interacting within the viral-cell recognition sites. Objective: This paper aims to evaluate the formation of complexes between the latest structural data available on the range of monkeypox and HSV-1/2 envelope proteins with the approved PSs protoporphyrin IX, chlorin e6, and methylene blue. Methods: Ligands and receptors preparation, and molecular docking analyses were performed with Chimera and the Autodock Vina Software. Molecular docking and molecular dynamics simulation (MD) analyses for a 100 ns trajectory were also performed for the p37 – Methylene blue complex. Results: PSs studies were found to form complexes into the patch regions of recognition between HSV-1/2 gD and human receptors, while MB was found to form a complex with the p37 protein into de pocket region where tecovirimat acts. MD simulation showed stability in the interaction of MB with the pocket region of the p37 protein. Conclusion: The molecular mechanisms of potential dual antiviral activity for these complexes were clarified showing that MI with the use of these PSs could be further evaluated for viral skin lesions produced by monkeypox and HSV.

Treatment of Helicobacter pylori (H. pylori) infections faces challenges such as drug adherence, drug resistance, and re-infection. Surface antigens like BabA and SabA cause the disease, while phytochemicals like glycyrrhizin and cinnamaldehyde in liquorice and cinnamon are highly absorbed by H. pylori. Other molecules like coumarin can disrupt H. pylori adherence. Optimizing pharmacokinetics of certain drugs remain a challenge. Plant-derived chemical compounds can overcome treatment restrictions using molecular docking research, drug compatibility, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) examinations. These tools help to determine the appropriate usage of phytochemicals in bacteria. Our work aims to explore the potential of phytochemicals (glycyrrhizin, cinnamaldehyde, coumarin) as a treatment for H. pylori disease using molecular docking (BabA, SabA, CagA, VacA and urease) and ADMET analysis by in silico approaches. Glycyrrhizin has the most favorable binding energies with both CagA (− 8.9 kcal/mol) and VacA (− 8.4 kcal/mol), indicating stable interactions. Cinnamaldehyde and coumarin show weaker binding energies, suggesting less stability. Amoxicillin and clarithromycin showed moderate binding energy. Glycyrrhizin, cinnamaldehyde, and coumarin showed non-toxicity in assays, while amoxicillin and clarithromycin displayed toxicity, underscoring the importance of thorough safety assessments in drug development by ADMET study. Compounds meeting Lipinski's Rule of Five criteria, including cinnamaldehyde and coumarin, demonstrate potential for good oral bioavailability. Despite these difficulties, substances like coumarin, glycyrrhizin, and cinnamondehyde can be useful in the treatment of H. pylori. In-depth safety evaluations and continuous research are essential for improving medication development and promoting more effective H. pylori treatment.Graphical

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine kinase that acts as a tumor suppressor and controls tumor growth in the early stages. However, its role in promoting tumor epithelial-mesenchymal transition (EMT) and stem cell expression becomes particularly significant in advanced-stage cancers, such as colon and thyroid cancer. The inhibition of DAPK1 might be beneficial to treat cancer. Our research focused on creating a first-in-class, small-molecule DAPK1 inhibitor for cancer therapy. In the present study, we have used a synthesized molecule, N-cyclohexylacrylamide (NCA), to identify DAPK1 and associated protein groups. We obtained the 3D protein structures from the protein data bank. Furthermore, ADMET and drug-likeness properties of the compound were analyzed by using the rules of Lipinski, Veber, and Ghose (http://www.swissadme.ch/). In addition, molecular docking analyses were performed with DAPK1 and related other proteins. In addition, molecular docking and dynamic analyses were performed with DAPK1 and related other proteins. The obtained results showed that NCA would be used in drug development for various diseases.