Binding Free Energy Values Research Articles

A Synergistic Interaction Between Citrus Hystrix Peel Essential Oil and Tetracycline and Evaluation of their Antibacterial Mechanism of Action in Vitro and in Silico Against Escherichia Coli.

Citrus hystrix essential oil (CHEO) have shown various pharmacological properties including antibacterial activity. This EO also possessed antibacterial effect against foodborne pathogens. There is less information available about the synergy interaction between CHEO and tetracycline, as well as their mechanism of action. Therefore, this study was conducted to evaluate the synergistic effect of CHEO and tetracycline against clinical isolate of Escherichia coli. Antibiofilm, bacteriolytic, and efflux pump inhibitor activities were also performed. The chemical composition of CHEO was analysed using GC-MS. Three major compounds, D-limonene (25.02 %), β-pinene (23.37 %), and β-sabinene (22.20 %) were identified. CHEO exhibited moderate antibacterial activity with MIC value of 250 μg/mL. The combination of CHEO (7.8 μg/mL) and tetracycline (62.5 μg/mL) produced a synergistic effect on E. coli with fractional inhibitory concentration index of 0.5. This mixture inhibited biofilm formation in E. coli. The combination of 7.8 μg/mL CHEO and 62.5 μg/mL tetracycline demonstrated bacteriolytic activity. In addition, the CHEO at 250 μg/mL showed a significant effect in inhibiting efflux pump. D-limonene has a binding free energy value of -20.13 kcal/mol with ompA transmembrane domain of E. coli. This finding indicates that CHEO has a potency to be developed as natural antibacterial against E. coli.

Evaluation of tamoxifen analogues as potential estrogen receptor alpha inhibitors for breast cancer treatment: A computational approach

Estrogen receptors, particularly ERα, play a key role in breast cancer progression, making them prime targets for therapeutic intervention. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been widely used for the treatment of ER+ breast cancer; however, its clinical application is limited by side effects and the emergence of resistance. This study aims to identify and evaluate TAM analogues with improved efficacy and reduced side effects by employing molecular docking and molecular dynamics (MD) simulations. Droloxifene, endoxifen, and afimoxifene emerged as promising candidates, exhibiting strong binding affinities with ERα, as indicated by highly negative binding energy (BE) values in docking simulations. MD simulations further validated the stability of the complexes formed between these analogues and ERα, with low root mean square deviation (RMSD) values and stable radius of gyration (Rg) profiles. Root mean square fluctuation (RMSF) analysis revealed balanced flexibility, with droloxifene and afimoxifene showing optimized flexibility for stable binding. Hydrogen bond analysis indicated more stable interactions between these analogues and ERα compared to TAM, suggesting enhanced binding affinity. MM/GBSA binding free energy analysis confirmed the high affinity of these analogues, with droloxifene displaying the most effective binding free energy (ΔGtotal) value. ADMET profiling suggests that droloxifene and endoxifen have superior pharmacokinetic properties relative to TAM. Overall, droloxifene, endoxifen, and afimoxifene represent promising alternatives to TAM, with the potential for further clinical development in breast cancer treatment. Experimental validation in cell-based and in vivo models will be crucial in future studies to confirm their efficacy and safety profiles.

Studi Molecular Docking dan Evaluasi Farmakokinetik Senyawa Analog Pirazol Turunan Benzen-Sulfonilurea sebagai Inhibitor Enzim Aldose Reduktase and α-Glukosidase Menggunakan Pendekatan In Silico

The pyrazole scaffold modification in various chemical structures on several studies has shown various biopharmacological activities. This study aims to predict the potential inhibition of pyrazole analogs derived benzene-sulfonylurea (4A, 4B, 4E, 5A, 5C, 5D) against the α-glucosidase (3A4A) and aldose reductase (3RX2) enzymes based on a molecular docking approach using Molecular Operating Environment (MOE) 2020.0102 software and evaluate pharmacokinetic profile (ADMET). In this study, the six test compounds were obtained from previous studies that have been proven antihyperglycemic. The results showed that all the 3,5-disubstituted benzene-sulfonylurea derivative pyrazole analogs are predicted to have low inhibitory activity against the α-glucosidase enzyme. Further, all compounds showed good aldose reductase inhibitor activity and had lower binding free energy values ​​than tolrestat as the positive control (-6.82 kcal/mol). Compound 5C has the best potential inhibitory activity against the aldose reductase enzyme compared to the other test compounds, because it has the lowest binding free energy value (-8.76 kcal/mol) and interacts with important residues on the receptor forming four hydrogen bonds, namely the carbonyl group of SO2 with residues Trp111 and His110, and the carbonyl group of the amide with residues His110 and Tyr48, as well as 3 hydrophobic bonds, namely a pyrazole ring with residues Leu300, Trp219 and a furan ring with Phe122. ADMET properties of the compounds are also predicted. This information provides an opportunity for a 5C compound as an aldose reductase inhibitor agent to develop drug candidates with better and safer activities.

Network Pharmacology Integrated With Quantum‐Polarized Ligand Docking and Molecular Simulation Revealed the Anti‐Diabetic Potential of Curcumin

AbstractDiabetes mellitus is a chronic metabolic disorder affecting millions of people worldwide and causes serious complications such as diabetic nephropathy. Curcumin, a natural polyphenol derived from turmeric, has demonstrated antidiabetic, anti‐inflammatory, and antioxidant properties. However, the molecular mechanisms underlying curcumin's anti‐diabetic effects remain incompletely understood. This study employed network pharmacology, molecular docking, and simulation techniques to explore the potential targets, and key pathways of curcumin in the treatment of diabetes. Using SwissTarget prediction and Superpred databases, we predicted the molecular targets for curcumin, while diabetes‐associated genes were obtained from DisGeNet. We identified 60 common targets for curcumin in diabetes. Protein‐protein interaction (PPI) analysis revealed three sub‐networks and ten hub genes with AKT1, TNF‐α, EGFR, and STAT3 identified as key hub genes that could serve as potential biomarkers. Gene enrichment analysis indicated that these genes primarily regulate insulin resistance and other metabolic pathways. Quantum‐polarized ligand docking (QPLD) showed that curcumin establishes multiple hydrogen and hydrophobic interactions with the essential amino acids of these hub targets. Molecular simulation results demonstrated stable dynamic behavior, a compact structure, and variations in residue flexibility. Binding free energy calculations using MM/GBSA and MM/PBSA methods validate curcumin's strong binding to the potential targets. Total binding free energy using MM/GBSA ranged from −21.35 to −30.94 kcal/mol while MM/PBSA calculations showed total binding free energy values between −19.80 and −26.66 kcal/mol. Altogether, this study provides valuable insights into the molecular targets of curcumin in diabetes and lays the foundation for future advancements in diabetes treatment.

Nucleic acid binding affinity and antioxidant activity of N-m-Tolyl-4-Chlorophenoxyacetohydroxamicacid.

Hydroxamic acids represent a group of weak organic acids, both naturally occurring and synthetically derived, characterized by the general formula RC(= O)N(R'OH). In this study, we investigated the binding behavior of N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) through a combination of techniques including UV-visible spectroscopy, fluorescence emission analysis, viscometry, and computational simulations using AutoDock4 software. Our findings reveal that the mode of binding between the compound and the nucleic acids is consistent with intercalation. Competitive binding experiments demonstrated that the complex competes effectively with ethidium bromide (EB) for binding to ct-DNA/t-RNA, displacing EB from its binding sites. Additionally, the introduction of the compound into the DNA-EB system resulted in a quenching of fluorescence emission peaks. Analysis of absorption spectra indicated a red shift and hypochromic shift when the compound interacted with DNA, further supporting the intercalative binding mode. The calculated binding constant (Kb) value for the compound is 6.62 × 104M-1 and 5.40 × 103M-1 indicating a strong interaction with ct-DNA and t-RNA respectively. We determined the Stern-Volmer constants for ct-DNA and t-RNA as 9.96 × 104M-1 and 8.13 × 105M-1, respectively. The binding free energy values for ct-DNA/t-RNA were calculated to be -3.741 × 107 and -5.425 × 108kcal/mol, respectively. Viscometric studies corroborated the UV results, showing a continuous increase in relative viscosity of ct-DNA/t-RNA solutions with the addition of the optimal hydroxamic acid concentration. Furthermore, we assessed the antioxidant activity of the compound using DPPH-radical scavenging and β-carotene linoleic acid assays. Gel electrophoresis results demonstrated the compound's remarkable efficacy in preventing DNA damage. Collectively, all experimental evidence supports the conclusion that N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid binds to ct-DNA/t-RNA through an intercalative mechanism, which is consistent with our molecular docking simulations.

A Method for Treating Significant Conformational Changes in Alchemical Free Energy Simulations of Protein-Ligand Binding.

Relative binding free energy (RBFE) simulation is a rigorous approach to the calculation of quantitatively accurate binding free energy values for protein-ligand binding in which a reference binder is gradually converted to a target binder through alchemical transformation during the simulation. The success of such simulations relies on being able to accurately sample the correct conformational phase space for each alchemical state; however, this becomes a challenge when a significant conformation change occurs between the reference and target binder-receptor complexes. Increasing the simulation time and using enhanced sampling methods can be helpful, but effects can be limited, especially when the free energy barrier between conformations is high or when the correct target complex conformation is difficult to find and maintain. Current RBFE protocols seed the reference complex structure into every alchemical window of the simulation. In our study, we describe an improved protocol in which the reference structure is seeded into the first half of the alchemical windows, and the target structure is seeded into the second half of the alchemical windows. By applying information about the relevant correct end point conformations to different simulation windows from the beginning, the need for large barrier crossings or simulation prediction of the correct structures during an alchemical simulation is in many cases obviated. In the diverse cases we examine below, the simulations yielded free energy predictions that are satisfactory as compared to experiment and superior to running the simulations utilizing the conventional protocol. The method is straightforward to implement for publicly available FEP workflows.

Bioprospection for antiviral compounds from selected medicinal plants against RNA polymerase of rotavirus A using molecular modelling and density functional theory

Rotavirus A (RVA) infection remains a significant global health challenge, especially in developing countries, causing severe dehydrating diarrhoea in children under five years of age. Despite the availability of four World Health Organization (WHO) pre-qualified vaccines, their availability, particularly in low-income countries, pose significant challenges. Currently, there are no specific anti-rotaviral medications hence, the urgency to develop novel therapeutics against rotavirus infection. Thus, this study explored the potential of secondary metabolites of Spondias mombin, Macaranga barteri and Dicerocaryum eriocarpum as novel inhibitors of the RNA-dependent RNA polymerase (VP1) of rotavirus A using computational techniques. Pharmacokinetics parameters were adopted to screen the top 20 metabolites with high affinity for the target, initially identified through a docking study. Furthermore, the ability of the resulting compounds to modulate the investigated target was assessed using molecular dynamics (MD) simulation, while density functional theory (DFT) calculations were conducted to predict the molecular properties of the top-ranked compounds. Except for ellagic acid hexoside (-33.14 kcal/mol), all the leads had higher binding free energy values relative to sofosbuvir (-36.58 kcal/mol) following a 120 ns MD simulation. Overall, the resulting complexes with the lead compounds demonstrated acceptable stability, reduced flexibility and compactness, with spiraeoside (-51.02 kcal/mol) displaying more favourable thermodynamics metrics, albeit with a lesser binding free energy relative to chrysoeriol 7-glucuronide (-58.36 kcal/mol). The binding free energy and thermodynamic parameters of the top-hit compounds could be attributed to their respective bond interactions and molecular orbital properties except chrysoeriol 7-glucuronide, with a need for additional structural adjustment to enhance its thermodynamic properties. Thus, these findings indicate the potential modulatory ability of the lead compounds against the VP1 protein of RVA, underscoring the importance of further in vitro and in vivo studies to validate the predicted activity, and ongoing efforts are being made to pursue this line of investigation.

Antimicrobial Potential of Calotropis gigantea Leaf Against Klebsiella pneumoniae in Ventilator-Associated Pneumonia

Calotropis gigantea or biduri has traditional medicinal properties. However, the effect of C. gigantea leaves in assisting the function of antibiotic-resistant ventilator-associated pneumonia (VAP), particularly caused by Klebsiella pneumoniae, has not been evaluated. The purpose of this study was to identify the active compounds of C. gigantea leaf extracts growing in the coastal area of Alue Naga, Banda Aceh, Indonesia, and assess its antimicrobial potential in preventing microbial resistance. C. gigantea leaves were extracted using three different solvents: ethanol, ethyl acetate, and n-hexane. The three extracts of C. gigantea leaves were analyzed for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, and the active compounds of C. gigantea were identified using gas chromatography-mass spectroscopy (GC-MS). The dominant bioactive compounds of the C. gigantea extract were enrolled for molecular docking analysis. The results of this study showed that the inhibitory concentration 50% (IC50) of the ethanol extract had a higher antioxidant activity (IC50 value of 3.3 ppm) than the ethyl acetate (IC50 value of 22.97 ppm) and n-hexane (IC50 value of 32.9 ppm). Bioactive compound identification using GC-MS from the three extracts showed similar dominant compounds, which were α-amyrin and lup-20(29)-en-3-ol, and these compounds belonged to the class of triterpenoid derivative compounds. Molecular docking analysis showed that α-amyrin (-9.6 Kcal/mol), β-amyrin (-9.6 Kcal/mol), and epilupeol (-9.2 Kcal/mol) in C. gigantea leaves had higher binding free energy values compared to cefixime (-8.7 Kcal/mol). Thus, it could be concluded that C. gigantea leaf extract is assumed to have great potential as an antimicrobial agent and in preventing microbial resistance, particularly in cases of VAP caused by Klebsiella pneumoniae. Doi: 10.28991/HEF-2024-05-03-010 Full Text: PDF

Cheminformatics-based analysis identified (Z)-2-(2,5-dimethoxy benzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one as an inhibitor of Marburg replication by interacting with NP

The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family, a non-segmented negative-strand RNA virus. This article represents the computer-aided drug design (CADD) approach for identifying drug-like compounds that prevent the MARV virus disease by inhibiting nucleoprotein, which is responsible for their replication. This study used a wide range of in silico drug design techniques to identify potential drugs. Out of 368 natural compounds, 202 compounds passed ADMET, and molecular docking identified the top two molecules (CID: 1804018 and 5280520) with a high binding affinity of −6.77 and −6.672 kcal/mol, respectively. Both compounds showed interactions with the common amino acid residues SER_216, ARG_215, TYR_135, CYS_195, and ILE_108, which indicates that lead compounds and control ligands interact in the common active site/catalytic site of the protein. The negative binding free energies of CID: 1804018 and 5280520 were −66.01 and −31.29 kcal/mol, respectively. Two lead compounds were re-evaluated using MD modeling techniques, which confirmed CID: 1804018 as the most stable when complexed with the target protein. PC3 of the (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) was 8.74 %, whereas PC3 of the 2′-Hydroxydaidzein (CID: 5280520) was 11.25 %. In this study, (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) unveiled the significant stability of the proteins' binding site in ADMET, Molecular docking, MM-GBSA and MD simulation analysis studies, which also showed a high negative binding free energy value, confirming as the best drug candidate which is found in Angelica archangelica which may potentially inhibit the replication of MARV nucleoprotein.

Molecular docking of ferulic acid, bakuchiol and niazirin on peroxisome proliferator-activated receptor gamma (PPAR-γ) as anti-diabetic agents

Background: Diabetes mellitus remains one of the most dangerous illnesses worldwide. The PPAR-gamma protein plays a crucial role in lipid and carbohydrate metabolism, making it a key target for diabetes therapy. Research into plant-derived active compounds for diabetes treatment is increasingly important. Objective: This study aims to evaluate and analyze the interaction of ferulic acid, niazirin, and bakuchiol with the peroxisome proliferator-activated receptor gamma (PPAR-γ) protein using molecular docking. Methods: Molecular docking was employed to assess the interactions between ferulic acid, niazirin, bakuchiol, and the PPAR-γ protein (PDB ID: 2PRG). The analysis focused on binding free energy values, amino acid residue interactions, the number of hydrogen bonds, and bond distances, comparing these results to those of the native ligand and pioglitazone, a known anti-diabetic drug targeting PPAR-γ. Results: The binding free energies for the ferulic acid-PPAR-γ, bakuchiol-PPAR-γ, niazirin-PPAR-γ, native ligand-PPAR-γ, and pioglitazone-PPAR-γ complexes were -5.54 kcal/mol, -8.47 kcal/mol, -6.56 kcal/mol, -10.08 kcal/mol, and -9.94 kcal/mol, respectively. The amino acid residue similarity percentages with the native ligand were 18.18% for ferulic acid, 27.27% for bakuchiol, 18.18% for niazirin, and 81.82% for pioglitazone. The native ligand-2PRG and pioglitazone-2PRG complexes exhibited superior hydrogen bond numbers and shorter bond distances compared to the other compounds. Conclusion: Although bakuchiol showed the most promising interaction among the tested compounds, none surpassed the binding affinity and stability of the native ligand or pioglitazone. Further research is needed to optimize these compounds for potential anti-diabetic therapy.

Synthesis, QTAIM, anticancer activity analysis of pyrrole-imidazole/benzimidazole derivatives and investigation of their reactivity properties using DFT calculations and molecular docking

As part of our ongoing investigation into pyrrole derivatives, we here present the synthesis, spectroscopic characterization, QTAIM, reactivity, anticancer activity, and comparative experimental and computational analysis of pyrrole-imidazole ((3l), (3p)) and benzimidazole derivatives ((3h), (3i), (3j), (3k), (3m), (3n), (3o)). All synthesized compounds (3h-3p) have been well characterized by spectroscopic techniques (FT-IR, 1H and 13C NMR, Mass spectrometry). The experimental 1H and 13C NMR chemical shift values of synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives have been well corroborated with computed chemical shifts. The vibrational analysis for four derivatives of pyrrole-benzimidazole (3m), (3n), (3o), and pyrrole-imidazole (3p) has the suitability for dimer formation in solid state by intermolecular heteronuclear hydrogen bonding (N–H···O) and the interaction energy of dimers are calculated to be 10.88, 11.70, 9.89 and 10.72 kcal/mol, using DFT. After basis-set superposition error (BSSE) correction, the interaction energies of dimers were found to be 11.12, 12.11, 10.13, and 11.52 kcal/mol. Estimated intermolecular H-bond in (3m-3n) compounds were found to be -13.38, -12.86, -11.02, and -11.28 kJ/mol using QTAIM. All the synthetic pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives exhibit strong antileukemia activity in vitro against the proliferative cell line L1210 leukemia cells. A dataset of investigated compounds was subjected for molecular modelling simulation against three distinct proteins (SYK, PI3K, and BTK), which was found to be highly implicated in the favourable interaction between the compounds and their target proteins in every instance. The synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives shown favourable interactions with their target proteins, with high activity and binding free energy values falling between 15.22 and 13.43 and -7.4 and -9.8 kcal/mol, respectively. The structure of pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives is thoroughly examined, and several parameters are proposed here to improve their anticancer activity.

Zn(II) and Cd(II) complexes of dithiocarbamate ligands: synthesis, characterization, anticancer, and theoretical studies

ABSTRACT A potassium 4-(ethoxycarbonyl)phenyldithiocarbamate, (4-etphdtc), and 6-ethoxybenzothiazol)-dithiocarbamate, (6-etbedtc), ligands have been isolated and four metal dithiocarbamate complexes of the type [M(4-etphdtc)2] and [M(6-etbedtc)2] (M = Zn, Cd;) were synthesized and characterized by elemental analysis and spectroscopic techniques (FT-IR,1H and13C{1H}-NMR, HRMS, UV–vis). Thermogravimetric studies of all four complexes were performed and the final product of the thermal decomposition was metal sulfides. The theoretical study with density functional theory (DFT) has been utilized to optimize the structures of the complexes for HOMO–LUMO energy calculation. Non-bonding orbitals (NBO) analysis was performed to determine the numerous hyper-conjugative interactions responsible for the stability of the compound. In addition, Molecular Electrostatic Potential (MEP) analysis was conducted to identify the compounds’ electron-rich, electron-poor, reactive sites, and bonding characteristics. The Electron Localization Function (ELF), and AIM Charges are also calculated. In vitro cytotoxicity, the complexes were examined against cervical cancer cells (HeLa) to assess their reactivity. Molecular docking studies were conducted to confirm the biological activity by simulating the binding orientation and affinity of the ligands and their complexes against VEGFR-2 kinase, The investigated ligands interact with the binding site as; hydrophilic (Lys868, Glu885, His1026, Cys1045, and Asp1046) and hydrophobic (Val889 and Leu889) for 4-etphdtc; hydrophilic (Lys868, Glu885, Cys1045, and Asp1046) and hydrophobic (Val889, Leu889, Leu1035, and Phe1047) for 6-etphdtc. The calculated binding free energy values for Zn(4-etphdtc)2 and Zn(6-etphdtc)2complexes are – 9.700 kcal/mol, – 10.003 kcal/mol, respectively.

Identification of aryl hydrocarbon receptor allosteric antagonists from clinically approved drugs.

The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR-ARNT-DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS-B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.

Synthesis, Characterization, Molecular Docking, and Molecular Dynamics Studies of Schiff Bases of 2-Phenoxy-1-Phenyl-Ethanone as Antibacterial Agents

Background: The development of antimicrobial resistance and reduced discovery and commercialization of newer antibiotics point to the need for the discovery of novel anti-bacterial agents. Schiff bases are reported to possess a broad range of pharmacological activi-ties, which also include antibacterial activity. With this background, novel Schiff bases were synthesized. Aim: The present study aimed to synthesize novel Schiff bases of 2-phenoxy-1-phenyl-etha-none with aryl amines and evaluate their antibacterial activity. Methods: The desired Schiff bases were synthesized by condensing various aryl amines with 2-bromo-1-phenylethanone and characterized by physicochemical and spectral methods. The antibacterial activity of the synthesized Schiff bases was determined by the cup diffusion method. Molecular docking with Staphylococcus aureus tyrosyl-t-RNA synthetase (Protein Data Bank ID: 1JIJ) was performed using Autodock. Molecular dynamics simulation studies were performed using GROMACS. ADME analysis and drug-likeliness of the synthesized compounds were predicted using SwissADME. Protein-ligand interactions were studied using BIOVIA Discovery Studio Visualizer. Results: Out of the synthesized compounds, two compounds, sb_04 and sb_05, exhibited fair antibacterial activity. The compounds sb_04 and sb_05 exhibited better binding energy values than the original ligand of the target enzyme and comparable binding energy with ampicillin. The Autodock program estimated the binding free energy and inhibition constant values of compound sb_05 as -9.18 kcal/mol and 187.33 nM and for the compound sb_04 as -8.82 kcal/mol and 341.59 nM, respectively. The RMSD values of the compound sb_04 were stable throughout the duration of the simulation; however, the compound sb_05 showed lesser sta-bility in the docked complex. Interestingly, the compound sb_05 (-182.754 kJ/mol) exhibited stable interaction with a lower value of total interaction energy than sb_04 (-136.304 kJ/mol). The synthesized Schiff bases showed no violation of Lipinski’s rule of five and a bioavailabil-ity score in the range of 55% to 85%. Conclusion: The synthesized Schiff bases present a scaffold for the development of novel antibacterial agents, in particular the compounds sb_04 and sb_05.

In-silico study unveils potential phytocompounds in Andrographis paniculata against E6 protein of the high-risk HPV-16 subtype for cervical cancer therapy

Despite therapeutic advancements, cervical cancer caused by high-risk subtypes of the human papillomavirus (HPV) remains a leading cause of cancer-related deaths among women worldwide. This study aimed to discover potential drug candidates from the Asian medicinal plant Andrographis paniculata, demonstrating efficacy against the E6 protein of high-risk HPV-16 subtype through an in-silico computational approach. The 3D structures of 32 compounds (selected from 42) derived from A. paniculata, exhibiting higher binding affinity, were obtained from the PubChem database. These structures underwent subsequent analysis and screening based on criteria including binding energy, molecular docking, drug likeness and toxicity prediction using computational techniques. Considering the spectrometry, pharmacokinetic properties, docking results, drug likeliness, and toxicological effects, five compounds—stigmasterol, 1H-Indole-3-carboxylic acid, 5-methoxy-, methyl ester (AP7), andrographolide, apigenin and wogonin—were selected as the potential inhibitors against the E6 protein of HPV-16. We also performed 200 ns molecular dynamics simulations of the compounds to analyze their stability and interactions as protein–ligand complexes using imiquimod (CID-57469) as a control. Screened compounds showed favorable characteristics, including stable root mean square deviation values, minimal root mean square fluctuations and consistent radius of gyration values. Intermolecular interactions, such as hydrogen bonds and hydrophobic contacts, were sustained throughout the simulations. The compounds displayed potential affinity, as indicated by negative binding free energy values. Overall, findings of this study suggest that the selected compounds have the potential to act as inhibitors against the E6 protein of HPV-16, offering promising prospects for the treatment and management of CC.

<i>De novo</i> design and virtual screening of potential Bcr-Abl tyrosine kinase inhibitors using deep learning and molecular modeling technologies

De novo design and virtual screening of small-molecule compounds with a high potential inhibitory activity against the Bcr-Abl tyrosine kinase playing a key role in the pathogenesis of chronic myeloid leukemia (CML) were carried out by an integrated computational approach including technologies of deep learning and molecular modeling. As a result, according to the calculation data we identified 5 compounds exhibiting low values of binding free energy to the enzyme comparable with those predicted for imatinib, nilotinib and ponatinib, anticancer drugs widely used in the clinic to treat patients with CML. It was shown that these compounds are able to form stable complexes with the ATP-binding sites of the Bcr-Abl tyrosine kinase and its mutant form T315I, which is confirmed by the analysis of the profiles of binding affinity and intermolecular interactions responsible for their energy stabilization. Based on the obtained data, these compounds, which have been generated by the deep learning neural network, are assumed to form promising basic structures for development of new effective drugs for treatment of patients with CML.

Computational Exploration of Potential Pharmacological Inhibitors Targeting the Envelope Protein of the Kyasanur Forest Disease Virus.

The limitations of the current vaccination strategy for the Kyasanur Forest Disease virus (KFDV) underscore the critical need for effective antiviral treatments, highlighting the crucial importance of exploring novel therapeutic approaches through in silico drug design. Kyasanur Forest Disease, caused by KFDV, is a tick-borne disease with a mortality of 3-5% and an annual incidence of 400 to 500 cases. In the early stage of infection, the envelope protein plays a crucial role by facilitating host-virus interactions. The objective of this research is to develop effective antivirals targeting the envelope protein to disrupt the virus-host interaction. In line with this, the 3D structure of the envelope protein was modeled and refined through molecular modeling techniques, and subsequently, ligands were designed via de novo design and pharmacophore screening, yielding 12 potential hits followed by ADMET analysis. The top five candidates underwent geometry optimization and molecular docking. Notably, compounds L4 (SA28) and L3 (CNP0247967) are predicted to have significant binding affinities of -8.91 and -7.58 kcal/mol, respectively, toward the envelope protein, based on computational models. Both compounds demonstrated stability during 200 ns molecular dynamics simulations, and the MM-GBSA binding free-energy values were -85.26 ± 4.63 kcal/mol and -66.60 ± 2.92 kcal/mol for the envelope protein L3 and L4 complexes, respectively. Based on the computational prediction, it is suggested that both compounds have potential as drug candidates for controlling host-virus interactions by targeting the envelope protein. Further validation through in-vitro assays would complement the findings of the present in silico investigations.

Molecular insight into the role of isoflavones targeting estrogen β receptor in diabetic wound healing pathway: A computational and in-vitro studies

This study aims to investigate the modulation of ER-β by phytoestrogens (isoflavones) in target diabetic wound healing using computational tools and in vitro studies. One of the primary limitations associated with delayed wound healing is inhibiting antioxidant pathways mediated by estrogen receptor-β (ER-β). In this study, we screened 50 isoflavones against the active pocket of ER-β (5TOA.pdb). Through the XP docking score, we evaluated the binding pattern and dynamic changes of the top 5 isoflavones having the highest docking scores, binding energy, and interactions with ER-β. Further, in vitro, MTT assay was performed on the L929 cell line, followed by scratch assay, DPPH assay and glucose uptake assay. The XP (Extra precision) docking score of the top 5 isoflavones were S-Equol −9.90, Genistein −9.71, Icaritin (ICT) −9.92, Biochanin A −8.97, and Formononetin −8.87 respectively when compared with standard estradiol −10.61 when docked with ER-β. The binding free energy values (ΔG bind) of the top 5 isoflavones were S-Equol (−27.15 kcal/mol), Genistein (−41.49 kcal/mol), ICT (−46.56 kcal/mol) Biochanin A (−37.01 kcal/Mol) and Formononetin (−42.96 kcal/Mol) respectively when compared with standard estradiol (−97.15 kcal/mol). Based on the XP glide score and free binding energy calculations, ICT was subjected to 100 ns MD simulation, confirming the stability of ICT with ER-β. The in-vitro results showed no cytotoxicity found up to 125 µM concentration, revealing normal proliferation of fibroblasts reduced total ROS production and prevented cell glucose uptake. These results highlighted the interaction potential of ICT for targeting ER-β, antioxidant, and anti-diabetic activity for diabetic wound healing.

Exploring Squalene's Impact on Epidermal Thickening and Collagen Production: Molecular Docking Insights

Background:: Aging is a progressive deterioration characterized by the gradual buildup of physiological alterations as time passes. The aging phenomenon encompasses various interconnected systems within the body, such as the skin, bones, cartilage, and hair. Objective and Methods: In this study, based on the appropriate properties of squalene, including antioxidant, anti-inflammatory, and skin repair properties, a molecular docking study was designed for the drug squalene and proteins related to the dermis and epidermis pathway and collagen production (including Col3A1, Col1A2, FBN1, Decorin, and HAS2). Results and Discussion:: The docking results indicated that the interaction of squalene with hyaluronan synthetase 2 (HAS2) possessed the highest negative binding free energy value of -10.90 KCal/mol, followed by decorin with a value of -9.99 KCal/mol. Also, the inhibition constant values of squalene- HAS2 and squalene-decorin complexes were equal to 1.61 and 7.51 μM, respectively. It has been stated that decorin (as a small proteoglycan) and HAS2 are involved in controlling the assembly of skin fibrils and the biosynthesis of glucosaminoglycans, respectively. Conclusion:: Considering that proteoglycans and glucosaminoglycans play a role in the skin aging process, squalene may be used as an anti-aging agent to induce these pathways and for different purposes. Squalene may be used as a potential agent alone or in combination with other compounds in tissue engineering scaffolds for cosmetic, anti-aging, wound healing, and tissue repair applications.

Molecular docking-based virtual screening and computational investigations of biomolecules (curcumin analogs) as potential lead inhibitors for SARS-CoV-2 papain-like protease

In the effort to combat SARS-CoV-2 infection, researchers are currently exploring the repurposing of conventional antiviral drugs, despite their limited efficacy. The SARS-CoV-2 virus encodes a papain-like protease (PLpro), which not only plays a crucial role in viral replication but also cleaves ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins, making it a prime target for the development of new antiviral medications. In this study, we conducted a multi-step in silico screening to identify novel, noncovalent PLpro inhibitors. Curcumin, an antioxidant derived from turmeric rhizomes (Curcuma longa L.), has undergone extensive preclinical investigations and shown significant efficacy against viruses and other ailments in both laboratory and animal studies. However, the pharmacological limitations of curcumin have prompted the synthesis of numerous novel curcumin analogs, necessitating evaluation for their therapeutic potential. The selectivity of the top-scoring compounds was assessed through molecular docking studies and molecular dynamics simulations to determine their binding affinity to PLpro. As a result, we identified 20 potential, selective PLpro inhibitors, from which the top two compounds (THA111 and THHGV6) were selected based on their binding free energy values towards PLpro as estimated by MM-PBSA calculations. These selected candidates demonstrate promising activity against the protein, with binding free energy values ranging from approximately −105 to −108 kJ/mol, and largely adopt a similar binding mode to known noncovalent SARS-CoV-2PLpro inhibitors (GRL0617 = −100.98 kJ/mol). We further propose these two most promising compounds for future in vitro evaluation. The findings for the top potential PLpro inhibitors have been deposited in a database (Curcumin Research Center) to aid research on anti-SARS-CoV-2 drugs.