Design of Novel Imidazole Derivatives as Potential Non-nucleoside Reverse Transcriptase Inhibitors Using Molecular Docking and Dynamics Strategies.

Human Immunodeficiency Virus (HIV) has become an epidemic causing Acquired Immunodeficiency Syndrome (AIDS). Highly active antiretroviral therapy (HAART) consists of Nucleoside Reverse Transcriptase Inhibitors (NRTIS), Nucleotide Reverse Transcriptase Inhibitors (NtRTIS), and Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIS) with HIV Protease Inhibitors (HIV PIs). However, the emergence of resistant strains of NNRTIS necessitates the search for better HIV-1-RT inhibitors. METHODS: In this study, a series of novel imidazoles (SP01-SP30) was designed using molecular docking inside the non-nucleoside inhibitory binding pocket (NNIBP) of the HIV-1-RT (PDB ID-1RT2) using Glide v13.0.137, Autodock Vina, and FlexX v2.1.3. Prime MMGBSA was used to study the free energy of binding of the inhibitors with the target enzyme. Molecular dynamics simulation studies were carried out to discover the dynamic behavior of the protein as well as to unveil the role of the essential amino acids required for the better binding affinity of the inhibitor within the NNIBP of the enzyme. The QikProp software module of Schrodinger and online SwissADME were also used to evaluate the drug-likeliness of these compounds. RESULTS: The imidazole derivative SP08 is predicted to be the most promising design compound that can be considered for further synthetic exploitations to obtain a molecule with the highest therapeutic index against HIV-1-RT. CONCLUSION: The results of the current study demonstrate the robustness of our in-silico drug design strategy that can be used for the discovery of novel HIV-1-RT inhibitors.

Integrated Exploration of Pyranocoumarin Derivatives as Synergistic Inhibitors of Dual-target for Mpro and PLpro Proteins of SARS-CoV-2 through Molecular Docking, ADMET Analysis, and Molecular Dynamics Simulation.

AIMS: This study aimed to explore the potential of natural anticoagulant compounds as synergistic inhibitors of the main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2 and find effective therapies against SARS-CoV-2 by investigating the inhibitory effects of natural anticoagulant compounds on key viral proteases. OBJECTIVE: The objectives of this study were to conduct rigorous virtual screening and molecular docking analyses to evaluate the binding affinities and interactions of selected anticoagulant compounds with Mpro and PLpro, to assess the pharmacokinetic and pharmacodynamic profiles of the compounds to determine their viability for therapeutic use, and to employ molecular dynamics simulations to understand the stability of the identified compounds over time. METHODS: In this study, a curated collection of natural anticoagulant compounds was conducted. Virtual screening and molecular docking analyses were performed to assess binding affinities and interactions with Mpro and PLpro. Furthermore, pharmacokinetic and pharmacodynamic analyses were carried out to evaluate absorption, distribution, metabolism, and excretion profiles. Molecular dynamics simulations were performed to elucidate compound stability. RESULTS: Natural compounds exhibiting significant inhibitory activity against Mpro and PLpro were identified. A dual-target approach was established as a promising strategy for attenuating viral replication and addressing coagulopathic complications associated with SARS-CoV-2 infection. CONCLUSION: The study lays a solid foundation for experimental validation and optimization of identified compounds, potentially leading to the development of precise treatments for SARS-CoV-2.

Novel quinoline-4-carboxamide derivatives potentiates apoptosis by targeting PDK1 to overcome chemo-resistance in colorectal cancer: Theoretical and experimental results.

A series of novel N,2-diphenyl-6-(aryl/heteroaryl)quinoline-4-carboxamide derivatives were designed and synthesized using the Suzuki coupling reaction and evaluated them for their anticancer activity. These compounds were screened for anti-colon cancer activity through in-silico studies by molecular docking and molecular dynamics studies. Furthermore, the density functional theory was used to determine the molecule's electrical properties. The molecular electrostatic potential map is used to evaluate the charge distribution on the molecule surface. Unveiling that the compound 7a (binding energy of -10.2 kcal/mol) has good inhibition activity compared to other synthesized compounds (7b-7j) as well as the standard drug Gefitinib. The stability of the compound 7a with the 1OKY protein was confirmed through molecular dynamics simulation studies, indicating potential anti-colon cancer activity against phosphoinositide dependent protein kinase-1 (PDK1). The in-silico ADMET pharmacokinetic properties indicate adherence to Lipinski's rule of five for favorable safety profiles and the compound falls within the optimal range for physicochemical and pharmacokinetic properties, which is comparable to that of the standard medication drug Gefitinib. The synthesized library of compounds was further evaluated for their in-vitro anticancer potency against colon, pancreatic and breast cancer cells. The results demonstrated that the compounds effectively suppressed the proliferative potential of the screened cells in a concentration-dependent manner, as revealed by MTT assay. The anticancer potential of these molecules was further evaluated by acridine orange/PI, and Hoechst/PI which demonstrates the potential of molecules to induce apoptosis in cancer cells. Further investigations and optimization of these derivatives could lead to the development of effective anticancer strategies.

QSPRmodeler - An open source application for molecular predictive analytics.

The drug design process can be successfully supported using a variety of in silico methods. Some of these are oriented toward molecular property prediction, which is a key step in the early drug discovery stage. Before experimental validation, drug candidates are usually compared with known experimental data. Technically, this can be achieved using machine learning approaches, in which selected experimental data are used to train the predictive models. The proposed Python software is designed for this purpose. It supports the entire workflow of molecular data processing, starting from raw data preparation followed by molecular descriptor creation and machine learning model training. The predictive capabilities of the resulting models were carefully validated internally and externally. These models can be easily applied to new compounds, including within more complex workflows involving generative approaches.

In-vitro and in-silico evaluation of rue herb for SARS-CoV-2 treatment.

SARS-CoV-2, a ß-coronavirus responsible for the COVID-19 pandemic, has resulted in approximately 4.9 million fatalities worldwide. Despite the urgent need, there is currently no specific therapeutic developed for treating or preventing SARS-CoV-2 infections. The virus enters the host by engaging in a molecular interaction between the viral Spike glycoprotein (S protein) and the host ACE2 receptor, facilitating membrane fusion and initiating infection. Inhibiting this interaction could impede viral activity. Therefore, this study aimed to identify natural small molecules from perennial rue herb (Ruta graveolens) as potential inhibitors against the S protein, thus preventing virus infection. Initially, a screening process was conducted on 53 compounds identified from rue herbs, utilizing pharmacophore-based virtual screening approaches. This analysis resulted in the identification of 12 hit compounds. Four compounds, namely Amentoflavone (CID: 5281600), Agathisflavone (CID: 5281599), Vitamin P (CID: 24832108), and Daphnoretin (CID: 5281406), emerged as potential S protein inhibitors through molecular docking simulations, exhibiting binding energies in kcal/mol of -9.2, -8.8, -8.2, and -8.0, respectively. ADMET analysis revealed favorable pharmacokinetics and toxicity profiles for these compounds. The compounds' stability with respect to the target S protein was evaluated using MD simulation and MM-GBSA approaches. The analysis revealed the stability of the selected compounds with the target protein. Also, PCA revealed distinctive movement patterns in four selected compounds, offered valuable insights into their functional behaviors and potential interactions. In-vitro assays revealed that rue herb extracts containing these compounds displayed potential inhibitory properties against the virus, with an IC50 value of 1.299 mg/mL and a cytotoxic concentration (CC50) value of 11.991 mg/mL. The compounds derived from rue herb, specifically Amentoflavone, Agathisflavone, Vitamin P, and Daphnoretin, show promise as candidates for the therapeutic intervention of SARS-CoV-2-related complications.

Potent α-glucosidase inhibitors with benzimidazole-propionitrile hybridization; synthesis, bioassay and docking study.

Background: Diabetes is characterized by a lack of insulin and insensitivity to insulin. In 2013, the global diabetes population was 382 million, with 90% of them having type 2 diabetes (non-insulin-dependent). It is predicted that this number will increase to 592 million by 2035.Aim: Here, we aimed to synthesize a series of benzimidazole-based derivatives B1-B32 with α-glucosidase inhibition potential as antidiabetic agents.Methods: Compounds B1-B32 were prepared in three three-step reactions, and the structures were elucidated using spectroscopic methods, namely 1H NMR, 13C NMR, MS and IR. Enzyme inhibition and kinetic study were done using commercial assay kits, and molecular docking study using autodock4.Results: Bioassay data showed that twenty-four out of the thirty-two tested compounds exhibited IC50 values ranging from 44 to 745 µM, surpassing the standard molecule, acarbose (IC50: 750 µM). it was determined that the best compound, B10, functions as a competitive inhibitor. Additionally, a molecular docking study provided insights into the interactions between the four most promising compounds (B5, B6, B10 and B28) and the active site residues within the enzyme.Conclusion: The tested compounds are interesting α-glucosidase inhibitors, which indicates the benefit of more bioassay studies, especially in vivo studies.

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Widely-targeted in silico and in vitro evaluation of veratrum alkaloid analogs as FAK inhibitors and dual targeting of FAK and Hh/SMO pathways for cancer therapy: A critical analysis.

Focal Adhesive Kinase (FAK), a key player in aggressive cancers, mediates signals crucial for progression, invasion, and metastasis. Despite advances in targeted therapies, drug resistance is still a challenge, and survival rates remain low, particularly for late-stage patients, emphasizing the need for innovative cancer therapeutics. Cyclopamine, a veratrum alkaloid, has shown promising anti-tumor properties, but the search for more potent analogs with enhanced affinity for the biological target continues. This study employs a hybrid virtual screening approach combining pharmacophore model-based virtual screening (PB-VS) and docking-based virtual screening (DB-VS) to identify potential inhibitors of the FAK catalytic domain. PB-VS on the PubChem database yielded a set of hits, which were then docked with the FAK catalytic domain in two stages (1st and 2nd DB-VS). Hits were ranked based on docking scores and interactions with the active site. The top three compounds underwent molecular dynamics simulations, alongside two control compounds (SMO inhibitor(s) and FAK inhibitor(s)), to assess stability through RMSD, RMSF, Rg, and SASA analyses. ADMET properties were evaluated, and compounds were filtered based on drug-likeness criteria. Molecular dynamics simulations demonstrated the stability of compounds when complexed with the FAK catalytic domain. Compounds 16 (-25 kcal/mol), 88 (-27.47 kcal/mol), and 87 (-18.94 kcal/mol) exhibited comparable docking scores, interaction profiles, stability, and binding energies, indicating their potential as lead candidates. However, further validation and optimization through quantitative structure-activity relationship (QSAR) studies are essential to refine their efficacy and therapeutic potential. The in vitro cell-based assay demonstrated that compound 101PF, a FAK inhibitor, significantly inhibited the proliferation and migration of A549 cells. However, the results regarding the combined effects of FAK and SMO inhibitors were inconclusive, highlighting the need for further investigation. This study contributes to developing more effective anti-cancer drugs by improving the understanding of potential cyclopamine-based veratrum alkaloid analogs with enhanced interactions with the FAK catalytic domain.

Bioefficacy, chromatographic profiling and drug-likeness analysis of flavonoids and terpenoids as potential inhibitors of H1N1 influenza viral proteins.

Considering medicinal plants, natural products present in these plants are the best sources of medications for combating viral infection. The possible drug target against viral H1N1 influenza proteins lead to identification of selected secondary metabolites from potential plants Tinospora cordifolia, Ocimum sanctum, and Piper nigrum. On analysis of in vitro cell based antiviral activity of the selected plant extracts, an indication for a possible lead compound against neuraminidase activity was evident. Potent ligands were selected using drug docking and ADMET analysis, and the screened lead metabolites were ultimately identified as terpenoid (Columbin) and, flavonoid (Cubebin, and Apigenin). Among the selected ligands, the drug binding activity of Cubebin with all the 6 proteins of H1N1 influenza type A virus, HA (4r8w), NA (4qn7), M2 (3lbw), PA (4wsb), PB1 (2znl) and PB2 (3wil), was pronounced. In addition, physicochemical and pharmacokinetic parameters linked to absorption, distribution, metabolism, excretion and toxicity (ADMET) have been evaluated and corroborate with our in vitro results. Molecular dynamics modelling indicated Cubebin can be a potential phytochemical in a drug discovery pipeline for the development of neuraminidase inhibitors. Further studies can provide a possibility for an alternative therapy against Influenza viruses.

Integration of 3D-QSAR, molecular docking, and machine learning techniques for rational design of nicotinamide-based SIRT2 inhibitors.

Selective inhibitors of sirtuin-2 (SIRT2) are increasingly recognized as potential therapeutics for cancer and neurodegenerative diseases. Derivatives of 5-((3-amidobenzyl)oxy)nicotinamides have been identified as some of the most potent and selective SIRT2 inhibitors reported to date (​Ai et al., 2016​; ​Ai et al., 2023​, ​Baroni et al., 2007​). In this study, a 3D-QSAR (3D-Quantitative Structure-Activity Relationship) model was developed using a dataset of 86 nicotinamide-based SIRT2 inhibitors from the literature, along with GRIND-derived pharmacophore models for selected inhibitors. External validation parameters emphasized the reliability of the 3D-QSAR model in predicting SIRT2 inhibition within the defined applicability domain. The interpretation of the 3D-QSAR model facilitated the generation of GRIND-derived pharmacophore models, which in turn enabled the design of novel SIRT2 inhibitors. Furthermore, based on molecular docking results for the SIRT1-3 isoforms, two classification models were developed: a SIRT1/2 model using the Naive Bayes algorithm and a SIRT2/3 model using the k-nearest neighbors algorithm, to predict the selectivity of inhibitors for SIRT1/2 and SIRT2/3. External validation parameters of the selectivity models confirmed their predictive power. Ultimately, the integration of 3D-QSAR, selectivity models and prediction of ADMET properties facilitated the identification of the most promising selective SIRT2 inhibitors for further development.

Design of novel potent selective survivin inhibitors using 2D-QSAR modeling, molecular docking, molecular dynamics, and ADMET properties of new MX-106 hydroxyquinoline scaffold derivatives.

Given the critical role of survivin (BIRC5) in tumor cell regulation, developing novel inhibitors represents a promising approach for cancer therapy. This study details the design of innovative survivin inhibitors based on the hydroxyquinoline scaffold of our previously reported lead compound, MX-106. Our study identified nine compounds whose inhibitory activity is expected to be superior to that of the most active molecule in the series. These compounds demonstrated potent suppression of MDA-MB-435 breast cancer cell proliferation in vitro and exhibited enhanced metabolic stability compared to the series' most active member. To evaluate these derivatives as potential survivin inhibitors, we employed a multi-faceted approach combining 2D-QSAR methods, molecular docking, molecular dynamics, and ADMET property assessment. Our molecular modeling studies led to the design of nine novel compounds (Pred1-Pred9) predicted to exhibit potent survivin inhibitory activity based on MLR models. To assess their suitability as drug candidates, we recommend a thorough evaluation of their ADMET properties. These compounds hold promise as innovative anticancer agents targeting survivin, similar to the established MX-106.

In silico design and ADMET evaluation of new inhibitors for PIM1 kinase using QSAR studies, molecular docking, and molecular dynamic simulation.

The proviral Integration site of Moloney (PIM) kinase is highly expressed in various diseases, including cancer, making the development of selective inhibitors for this protein important. A series of PIM1 inhibitors, triazolo [4, 3-b] pyridazin-3-yl-quinoline derivatives, have been studied to design new inhibitors. The activity and structural features of these derivatives were investigated to understand their interactions with PIM1 using molecular docking, molecular dynamic simulation, and QSAR techniques. In a study of 30 compounds using the structure-activity technique and the MLR method, a linear model with R2 train = 0.91 and R2 test = 0.96 was obtained. The model utilized descriptors such as RDF080v, RDF105v, RDF135v, Mor03v, and H046 to express the structural characteristics of the inhibitors. To enhance the model, the SVR non-linear method with the RBF function was also used, resulting in an improved model with R2 train = 0.98 and R2 test = 0.98. Furthermore, the molecular docking technique was employed to investigate the interaction of compounds with high (compound 25) and low (compound 13) inhibitory activity. It was observed that the rings with nitrogen atoms interacted with the protein. The molecular binding results indicate that groups such as OMe and rings with Nitrogen can enhance the inhibitory activity of the compounds. Additionally, oxygen and nitrogen atoms contribute to an increased number of hydrogen bonds, thereby increasing the inhibitory activity of the compounds. Additionally, the stability and bonding modes of active and inactive compounds were studied using molecular dynamic simulation. Based on the results, four new inhibitors were designed, demonstrating better inhibition efficiency with the PIM1 kinase compared to the reference compounds. Moreover, the designed compounds underwent evaluation for ADMET, yielding promising results.

Network analysis and molecular modeling studies of pinocembrin a bioactive phytochemical of Dodonaea viscosa against Parkinson's disease.

Parkinson's disease, a neurodegenerative disorder, is quickly progressing and accounts for 15% of dementia cases. Parkinson's disease is the second most frequent form of neuronal degeneration after Alzheimer's, with an average age of 55 years for individuals exhibiting neuropsychiatric and physiological symptoms. Due to the effectiveness, low toxicity, and low side effects, bioactive compounds from plants have received increased attention recently as therapeutic drugs. In the current study, effective anti-neurodegenerative phytochemicals from Dodonaea viscosa were screened using in silico methods and have been proposed to be further investigated for the treatment of Parkinson's disease. The structures of twenty bioactive chemicals were screened and graph theoretical network analysis revealed alpha-synuclein as a potent therapeutic target. Based on docking scores, an effective bioactive molecule was selected, and its energy values, electrostatic potential surface and drug-like qualities were examined using molecular orbitals, pharmacokinetics and toxicity studies. Pinocembrin was found as a superior binder based on molecular docking as it demonstrated stronger binding with - 10.2 kcal/mol. An investigation using Ramachandran plot validated the protein-ligand complex secondary structure's stability. Pinocembrin, a bioactive phytochemical from Dodonaea viscosa, may be a viable lead molecule that may be developed as a candidate medicine for anti-neurodegenerative therapy against Parkinson's disease.

Comparative evaluation of anticancer potential of Spilanthes paniculata leaf and flower essential oil using annexin V and orosphere formation in oral cancer cell line.

Spilanthes paniculata, a member of the Asteraceae family, is predominantly used as a traditional remedy in addressing oral ailments, particularly gum infections and sore throat. The flowers are chewed to alleviate toothache immediately. This study evaluated a comparison between the essential oils of leaf and flower derived from Spilanthes paniculata targeting the SCC9 oral cell lines using in vitro and in silico approaches. The anticancer activity was performed through an MTT assay, apoptosis assays using annexin V and orospheres formation assays. Molecular docking was performed between five selected phytocompounds against the p53 protein by using AutoDock 4.2.6 software. The results confirmed that the flower essential oil significantly reduced the cell viability in a dose-dependent manner, with an IC50 value of 113.95 µg/mL. The apoptosis assays showed that the flower essential oil was approximately 2.5 times more effective in inducing early apoptosis at 50 µg/mL compared to the essential oil of the leaf. The orosphere formation assays further confirmed the anticancer potential of the flower essential oil. Spathulenol exhibited strong hydrogen bonding with the p53 protein. The ADMET prediction tools were used to predict the in silico pharmacokinetics and drug-like properties of the phytoconstituents. The results suggested that Spathulenol and Nerolidol have high gastrointestinal absorption (GIA), with estimated solubility (ESOL) values of - 3.17 and - 3.22, respectively, falling within the optimal range. These findings suggest that the flower's essential oil efficiently prevented the proliferation of oral cancer and observed a notable degree of cell death, inducing apoptosis and suggesting its significant antiproliferative activity against cancerous cell line which could be explored further for therapeutic applications.

Tyramine Derivatives as Versatile Pharmacophores With Potent Biological Properties: Sex Hormone-Binding Globulin Inhibition, Colon Cancer Antimigration, and Antimicrobial Activity.

Guided by the idea that the presence of a heterocyclic aromatic core and tyramine moiety, under the umbrella of a single molecular scaffold could bring interesting biological properties, herein we present synthesis, characterization, with two crystal structures reported, and biological evaluation of some tyramine derivates. Cytotoxic and antimigratory potential was addressed by using a colorectal cancer cell line as a model system. Although possessing no cytotoxic effects, two compounds have shown strong antimigratory potential in low doses, with no effect on healthy MRC-5 cells. Evaluation of their antimicrobial activities suggested prominent antimicrobial activity, where Compound 4 outperformed streptomycin against Escherichia coli and Proteus mirabilis. Hormone-dependent types of cancer, such as prostate, ovary, and breast, are highly dependent on human sex hormone-binding globulin (SHBG) blood levels. A molecular docking study has shown that 1 has high affinity to bind and therefore compete with natural steroids for the SHBG steroid-binding site. DNA-binding study have shown that 4 interacts with CT-DNA in a groove-binding mode. In silico ADME/T study revealed that all compounds have suitable physicochemical properties for oral bioavailability and druglikeness, while toxicity tests for 1, 4, and 6 suggested potential for mutagenicity (4, 6), hepatotoxicity (6), and skin sensation (1).

Design, Synthesis, and Antimicrobial Evaluation of New Thiopyrimidine-Benzenesulfonamide Compounds.

Bacterial infection poses a serious threat to human life due to the rapidly growing resistance of bacteria to antibacterial drugs, which is a significant public health issue. This study was focused on the design and synthesis of a new series of 25 analogues bearing a 5-cyano-6-oxo-4-substituted phenyl-1,6-dihydropyrimidine scaffold hybridized with different substituted benzenesulfonamides through the thioacetamide linker M1-25. The antimicrobial activity of the new molecules was studied against various Gram-positive, Gram-negative, and fungal strains. All the tested compounds showed promising broad-spectrum antimicrobial efficacy, especially against K. pneumoniae and P. aeruginosa. Furthermore, the most promising compounds, 6M, 19M, 20M, and 25M, were subjected to minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. In addition, the antivirulence activity of the compounds was also examined using multiple biofilm assays. The new compounds promisingly revealed the suppression of microbial biofilm formation in the examined K. pneumoniae and P. aeruginosa microbial isolates. Additionally, in silico ADMET studies were conducted to determine their oral bioavailability, drug-likeness characteristics, and human toxicity risks. It is suggested that new pyrimidine-benzenesulfonamide derivatives may serve as model compounds for the further optimization and development of new antimicrobial and antisepsis candidates.

Low-Basicity 5-HT6 Receptor Ligands from the Group of Cyclic Arylguanidine Derivatives and Their Antiproliferative Activity Evaluation.

The serotonin 5-HT6 receptor (5-HT6R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT6R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT6R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT6R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug-drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio rerio model. Two antagonists with an affinity constant Ki < 50 nM (PR 68Ki = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug-drug interactions.

Antibacterial and Antibiofilm Potential of Chlorophyllin Against Streptococcus mutans In Vitro and In Silico.

BACKGROUND: Streptococcus mutans is a leading causative agent of dental caries and exerts pathogenicity by forming biofilms. Dental caries continues to be a significant public health issue worldwide, affecting an estimated 2.5 billion people, showing a 14.6% increase over the past decade. Herein, the antibacterial potential of Chlorophyllin extracted from Spinacia oleracea was evaluated against biofilm-forming S. mutans via in vitro and in silico studies. METHODOLOGY: The antimicrobial activity of chlorophyllin extract against S. mutans isolates was tested using the agar well diffusion method. Chlorophyllin extract was also tested against biofilm-forming isolates of S. mutans. Chlorophyllin was docked with the antigen I/II (AgI/II) protein of S. mutans to evaluate its antimicrobial mechanism. The chemical structure and canonical SMILES format of Chlorophyllin were obtained from PubChem. Additionally, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses of Chlorophyllin were performed using ADMETlab 2.0 to assess its pharmacokinetic properties. RESULTS: An agar well diffusion assay revealed that all S. mutans isolates were susceptible to Chlorophyllin extract and showed a variety of inhibition zones ranging from 32 to 41 mm. Chlorophyllin reduces the biofilm strength of four isolates from strong to moderate and six from strong to weak. The antibiofilm potential of Chlorophyllin was measured by a reduction in the number of functional groups observed in the Fourier Transform Infrared Spectrometer (FTIR) spectra of the extracellular polymeric substance (EPS) samples. Chlorophyllin showed binding with AgI/II proteins of S. mutans, which are involved in adherence to the tooth surface and initiating biofilm formation. The ADMET analysis revealed that the safety of Chlorophyllin exhibited favorable pharmacokinetic properties. CONCLUSIONS: Chlorophyllin stands out as a promising antibacterial and antibiofilm agent against biofilm-forming S. mutans, and its safety profile highlights its potential suitability for further investigation as a therapeutic agent.

In Silico Exploration of Novel EGFR Kinase Mutant-Selective Inhibitors Using a Hybrid Computational Approach.

Targeting epidermal growth factor receptor (EGFR) mutants is a promising strategy for treating non-small cell lung cancer (NSCLC). This study focused on the computational identification and characterization of potential EGFR mutant-selective inhibitors using pharmacophore design and validation by deep learning, virtual screening, ADMET (Absorption, distribution, metabolism, excretion and toxicity), and molecular docking-dynamics simulations. A pharmacophore model was generated using Pharmit based on the potent inhibitor JBJ-125, which targets the mutant EGFR (PDB 5D41) and is used for the virtual screening of the Zinc database. In total, 16 hits were retrieved from 13,127,550 molecules and 122,276,899 conformers. The pharmacophore model was validated via DeepCoy, generating 100 inactive decoy structures for each active molecule and ADMET tests were conducted using SWISS ADME and PROTOX 3.0. Filtered compounds underwent molecular docking studies using Glide, revealing promising interactions with the EGFR allosteric site along with better docking scores. Molecular dynamics (MD) simulations confirmed the stability of the docked conformations. These results bring out five novel compounds that can be evaluated as single agents or in combination with existing therapies, holding promise for treating the EGFR-mutant NSCLC.

Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency.

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thin-layer chromatography (RP-TLC) in an acetone-TRIS buffer (pH = 7.4). The relative lipophilicity parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter RM0 was transformed into parameter logPTLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski's rule of five, Ghose's rule and Veber's rule, confirming their bioavailability.

Modified oxymatrine as novel therapeutic inhibitors against Monkeypox and Marburg virus through computational drug design approaches.

Global impact of viral diseases specially Monkeypox (mpox) and Marburg virus, emphasizing the urgent need for effective drug interventions. Oxymatrine is an alkaloid which has been selected and modified using various functional groups to enhance its efficacy. The modifications were evaluated using various computatioanal analysis such as pass prediction, molecular docking, ADMET, and molecular dynamic simulation. Mpox and Marburg virus were chosen as target diseases based on their maximum pass prediction spectrum against viral disease. After that, molecular docking, dynamic simulation, DFT, calculation and ADMET prediction were determined. The main objective of this study was to enhance the efficacy of oxymatrine derivatives through functional group modifications and computational analyses to develop effective drug candidates against mpox and Marburg viruses. The calculated binding affinities indicated strong interactions against both mpox virus and Marburg virus. After that, the molecular dynamic simulation was conducted at 100 ns, which confirmed the stability of the binding interactions between the modified oxymatrine derivatives and target proteins. Then, the modified oxymatrine derivatives conducted theoretical ADMET profiling, which demonstrated their potential for effective drug development. Moreover, HOMO-LUMO calculation was performed to understand the chemical reactivity and physicochemical properties of compounds. This computational analysis indicated that modified oxymatrine derivatives for the treatment of mpox and Marburg virus suggested effective drug candidates based on their binding affinity, drug-like properties, stability and chemical reactivity. However, further experimental validation is necessary to confirm their clinical value and efficacy as therapeutic candidates.