Investigating the potential of 6-substituted 3-formyl chromone derivatives as anti-diabetic agents using in silico methods.

In exploring nature's potential in addressing diabetes-related conditions, this study investigates the therapeutic capabilities of 3-formyl chromone derivatives. Utilizing in silico methodologies, we focus on 6-substituted 3-formyl chromone derivatives (1-16) to assess their therapeutic potential in treating diabetes. The research examined the formyl group at the chromone's C-3 position. ADMET, biological activities, were conducted along with B3LYP calculations using 3 different basis sets. The analogues were analyzed based on their parent structure obtained from PubChem. The HOMO-LUMO gap confirmed the bioactive nature of the derivatives, NBO analysis was performed to understand the charge transfer. PASS prediction revealed that 3-formyl chromone derivatives are potent aldehyde oxidase inhibitors, insulin inhibitors, HIF1A expression inhibitors, and histidine kinase. Molecular docking studies indicated that the compounds had a strong binding affinity with proteins, including CAD, BHK, IDE, HIF-α, p53, COX, and Mpro of SARS-CoV2. 6-isopropyl-3-formyl chromone (4) displayed the highest affinity for IDE, with a binding energy of - 8.5 kcal mol-1. This result outperformed the affinity of the reference standard dapagliflozin (- 7.9 kcal mol-1) as well as two other compounds that target human IDE, namely vitexin (- 8.3 kcal mol-1) and myricetin (- 8.4 kcal mol-1). MD simulations were revealed RMSD value between 0.2 and 0.5 nm, indicating the strength of the protein-ligand complex at the active site.

In Silico Discovery and Predictive Modeling of Novel Acetylcholinesterase (AChE) Inhibitors for Alzheimer's Treatment.

INTRODUCTION: Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage. METHOD: This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aß, BChE, GSK-3ß, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme's pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives. RESULT: This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations. CONCLUSION: Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer's disease.

Design, synthesis, and bioevaluation of novel unsaturated cyanoacetamide derivatives: In vitro and in silico exploration.

In this study, we synthesized novel α,ß-unsaturated 2-cyanoacetamide derivatives (1-5) using microwave-assisted Knoevenagel condensation. Characterization of these compounds was carried out using FTIR and 1H NMR spectroscopy. We then evaluated their in vitro antibacterial activity against both gram-positive and gram-negative pathogenic bacteria. Additionally, we employed in silico methods, including ADMET prediction and density functional theory (DFT) calculations of molecular orbital properties, to investigate these cyanoacetamide derivatives (1-5). Molecular docking was used to assess the binding interactions of these derivatives (1-5) with seven target proteins (5MM8, 4NZZ, 7FEQ, 5NIJ, ITM2, 6SE1, and 5GVZ) and compared them to the reference standard tyrphostin AG99. Notably, derivative 5 exhibited the most favorable binding affinity, with a binding energy of -7.7 kcal mol-1 when interacting with the staphylococcus aureus (PDB:5MM8), while also meeting all drug-likeness criteria. Additionally, molecular dynamics simulations were carried out to evaluate the stability of the interaction between the protein and ligand, utilizing parameters such as Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), Radius of Gyration (Rg), and Principal Component Analysis (PCA). A 50 nanosecond molecular dynamics (MD) simulation was performed to investigate stability further, incorporating RMSD and RMSF analyses on compound 5 within the active binding site of the modeled protein across different temperatures (300, 305, 310, and 320 K). Among these temperatures, compound 5 exhibited an RMSD value ranging from approximately 0.2 to 0.3 nm at 310 K (body temperature) with the 5MM8 target, which differed from the other temperature conditions. The in silico results suggest that compound 5 maintained significant conformational stability throughout the 50 ns simulation period. It is consistent with its low docking energy and in vitro findings concerning α,ß-unsaturated cyanoacetamides. Key insights from this study include:•The creation of innovative α,ß-unsaturated 2-cyanoacetamide derivatives (1-5) employing cost-effective, licensed, versatile, and efficient software for both in silico and in vitro assessment of antibacterial activity.•Utilization of FTIR and NMR techniques for characterizing compounds 1-5.

Tolperisone hydrochloride improves motor functions in Parkinson's disease via MMP-9 inhibition and by downregulating p38 MAPK and ERK1/2 signaling cascade.

The mitogen-activated protein kinase (MAPK) signaling pathway, particularly the p38 MAPK and ERK1/2, has been implicated in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that MAPK signaling pathway can influence the expression of matrix metalloproteinase 9 (MMP-9), known for its involvement in various physiological and pathological processes, including neurodegenerative diseases. This study explores the modulation of MMP-9 expression via the MAPK/ERK signaling cascade and its potential therapeutic implications in the context of PD-associated motor dysfunction. Here, tolperisone hydrochloride (TL), a muscle relaxant that blocks voltage-gated sodium and calcium channels, was used as a treatment to observe its effect on MAPK signaling and MMP-9 expression. Rotenone (RT) exposure in mice resulted in a significant reduction in substantia nigra and primary motor cortex neurons, which were further evidenced by impairments in motor function. When TL was administered, neuron count was restored (89.0 ± 4.78 vs 117.0 ± 4.46/mm2), and most of the motor dysfunction was alleviated. Mechanistically, TL reduced the protein expression of phospho-p38MAPK (1.06 fold vs 1.00 fold) and phospho-ERK1/2 (1.16 fold vs 1.02 fold), leading to the inhibition of MAPK signaling, as well as reduced MMP-9 concentrations (2.76 ± 0.10 vs 1.94 ± 0.10 ng/mL) in the process of rescuing RT-induced neuronal cell death and motor dysfunction. Computational analysis further revealed TL's potential inhibitory properties against MMP-9 along with N and L-type calcium channels. These findings shed light on TL's neuroprotective effects via MMP-9 inhibition and MAPK signaling downregulation, offering potential therapeutic avenues for PD-associated motor dysfunction.

Exploring the anticancer and antibacterial potential of naphthoquinone derivatives: a comprehensive computational investigation.

This study investigates the potential of 2-(4-butylbenzyl)-3-hydroxynaphthalene-1,4-dione (11) and its 12 derivatives as anticancer and biofilm formation inhibitors for methicillin-resistant staphylococcus aureus using in silico methods. The study employed various computational methods, including molecular dynamics simulation molecular docking, density functional theory, and global chemical descriptors, to evaluate the interactions between the compounds and the target proteins. The docking results revealed that compounds 9, 11, 13, and ofloxacin exhibited binding affinities of -7.6, -7.9, -7.5, and -7.8 kcal mol-1, respectively, against peptide methionine sulfoxide reductase msrA/msrB (PDB: 3E0M). Ligand (11) showed better inhibition for methicillin-resistant staphylococcus aureus msrA/msrB enzyme. The complex of the 3E0M-ligand 11 remained highly stable across all tested temperatures (300, 305, 310, and 320 K). Principal Component Analysis (PCA) was employed to evaluate the behavior of the complex at various temperatures (300, 305, 310, and 320 K), demonstrating a total variance of 85%. Convergence was confirmed by the eigenvector's cosine content value of 0.43, consistently displaying low RMSD values, with the minimum observed at 310 K. Furthermore, ligand 11 emerges as the most promising candidate among the compounds examined, showcasing notable potential when considering a combination of in vitro, in vivo, and now in silico data. While the naphthoquinone derivative (11) remains the primary candidate based on comprehensive in silico studies, further analysis using Frontier molecular orbital (FMO) suggests while the Egap value of compound 11 (2.980 eV) and compound 13 (2.975 eV) is lower than ofloxacin (4.369 eV), indicating their potential, so it can be a statement that compound 13 can also be investigated in further research.

Exploring the effectiveness of flavone derivatives for treating liver diseases: Utilizing DFT, molecular docking, and molecular dynamics techniques.

In exploring nature's potential in addressing liver-related conditions, this study investigates the therapeutic capabilities of flavonoids. Utilizing in silico methodologies, we focus on flavone and its analogs (1-14) to assess their therapeutic potential in treating liver diseases. Molecular change calculations using density functional theory (DFT) were conducted on these compounds, accompanied by an evaluation of each analog's physiochemical and biochemical properties. The study further assesses these flavonoids' binding effectiveness and locations through molecular docking studies against six target proteins associated with human cancer. Tropoflavin and taxifolin served as reference drugs. The structurally modified flavone analogs (1-14) displayed a broad range of binding affinities, ranging from -7.0 to -9.4 kcal mol⁻¹, surpassing the reference drugs. Notably, flavonoid (7) exhibited significantly higher binding affinities with proteins Nrf2 (PDB:1 × 2 J) and DCK (PDB:1 × 2 J) (-9.4 and -8.1 kcal mol⁻¹) compared to tropoflavin (-9.3 and -8.0 kcal mol⁻¹) and taxifolin (-9.4 and -7.1 kcal mol⁻¹), respectively. Molecular dynamics (MD) simulations revealed that the docked complexes had a root mean square deviation (RMSD) value ranging from 0.05 to 0.2 nm and a root mean square fluctuation (RMSF) value between 0.35 and 1.3 nm during perturbation. The study concludes that 5,7-dihydroxyflavone (7) shows substantial promise as a potential therapeutic agent for liver-related conditions. However, further validation through in vitro and in vivo studies is necessary. Key insights from this study include:•Screening of flavanols and their derivatives to determine pharmacological and bioactive properties using ADMET, molinspiration, and pass prediction analysis.•Docking of shortlisted flavone derivatives with proteins having essential functions.•Analysis of the best protein-flavonoid docked complexes using molecular dynamics simulation to determine the flavonoid's efficiency and stability within a system.

Whole genome sequence of denitrifying bacterium Stutzerimonas stutzeri strain NGHE31, collected from an eutrophic wetland in Sunamganj, Bangladesh, following the 2017 flash floods.

Here, we report the whole genome sequence of Stutzerimonas stutzeri strain NGHE31, isolated from Dekhar Haor, following the 2017 flash flood that resulted in mass die-offs of local wildlife. The predicted genome size is 4,434,670 bp, with 63.97% GC content, 4,035 coding sequences, 3 rRNAs, and 50 tRNAs.

Synthesis of New Derivatives of Benzylidinemalononitrile and Ethyl 2-Cyano-3-phenylacrylate: In Silico Anticancer Evaluation.

In this study, microwave-assisted Knoevenagel condensation was used to produce two novel series of derivatives (1-6) from benzylidenemalononitrile and ethyl 2-cyano-3-phenylacrylate. The synthesized compounds were characterized using Fourier transform infrared (FT-IR) and 1H NMR spectroscopies. The pharmacodynamics, toxicity profiles, and biological activities of the compounds were evaluated through an in silico study using prediction of activity spectra for substances (PASS) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies. According to the PASS prediction results, compounds 1-6 showed greater antineoplastic potency for breast cancer than other types of cancer. Molecular docking was employed to investigate the binding mode and interaction sites of the derivatives (1-6) with three human cancer targets (HER2, EGFR, and human FPPS), and the protein-ligand interactions of these derivatives were compared to those reference standards Tyrphostin 1 (AG9) and Tyrphostin 23 (A23). Compound 3 showed a stronger effect on two cell lines (HER2 and FPPS) than the reference drugs. A 20 ns molecular dynamics (MD) simulation was also conducted to examine the ligand's behavior at the active binding site of the modeled protein, utilizing the lowest docking energy obtained from the molecular docking study. Enthalpies (ΔH), Gibbs free energies (ΔG), entropies (ΔS), and frontier molecular orbital parameters (highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap, hardness, and softness) were calculated to confirm the thermodynamic stability of all derivatives. The consistent results obtained from the in silico studies suggest that compound 3 has potential as a new anticancer and antiparasitic drug. Further research is required to validate its efficacy.

Comparisons of computational and experimental thermochemical properties of α-amino acids.

This study provides comprehensive benchmark calculations for the thermochemical properties of the common α-amino acids. Calculated properties include the proton affinity, gas-phase basicity, protonation entropy, ΔH°(acid), ΔG°(acid), and enthalpies of formation for the protonated and deprotonated α-amino acids. In order to determine the performance at various levels of theory, including density functional methods and composite methods, the calculated thermochemical properties are compared to experimental results. For all the common α-amino acids investigated, the thermochemical properties computed with the Gaussian-n theories were found to be quite consistent with each other in terms of mean absolute deviation from experiment. While all Gaussian-n theory values can serve as benchmarks, we focus on the G3MP2 values as it is the least resource-intensive of the Gaussian-n theories considered.

Computational study of the deamination of 8-oxoguanine.

Oxidation of guanine in DNA yields the nucleobase damage product 8-oxoguanine (8-oxoG), whose further oxidation gives other more stable products. In the present study, the mechanism for the deamination of 8-oxoG with H(2)O, 2H(2)O, H(2)O/OH(-), and 2H(2)O/OH(-) and for protonated 8-oxoG (8-oxoGH(+)) with H(2)O has been investigated using ab initio calculations. All structures were optimized at RHF/6-31G(d), MP2/6-31G(d), and B3LYP with the 6-31G(d), 6-31+G(d), 6-31G(d,p), 6-31+G(d,p), and 6-31++G(d.p) basis sets. Energies were determined at the G3MP2 level of theory, and solvent calculations were performed using both the polarizable continuum model (PCM) and the solvation model on density (SMD). Intrinsic reaction coordinate calculations were performed to characterize the transition states on the potential energy surface. Thermodynamic properties (ΔE, ΔH, and ΔG), activation energies, enthalpies, and Gibbs free energies of activation were also calculated for each reaction investigated. All pathways yield an initial tetrahedral intermediate and, in the final step, an intermediate that dissociates to products via a 1,3-proton shift. At the G3MP2 level of theory, deamination with H(2)O/OH(-) was found to have an overall activation energy of 187, 176, and 156 kJ mol(-1) for the gas phase, PCM, and SMD, respectively, which are ∼50 kJ mol(-1) lower than with H(2)O only. These barriers can be compared to those for the reaction of 8-oxoGH(+) with H(2)O of 248 kJ mol(-1) in the gas phase and 238 kJ mol(-1) in aqueous solution (PCM). The lowest overall activation energies (G3MP2) are for the deamination of 8-oxoG with 2H(2)O/OH(-), 134 kJ mol(-1) in the gas phase and 129 kJ mol(-1) with PCM.

Mechanistic study of the deamination reaction of guanine: a computational study.

The mechanism for the deamination of guanine with H(2)O, OH(-), H(2)O/OH(-) and for GuaH(+) with H(2)O has been investigated using ab initio calculations. Optimized geometries of the reactants, transition states, intermediates, and products were determined at RHF/6-31G(d), MP2/6-31G(d), B3LYP/6-31G(d), and B3LYP/6-31+G(d) levels of theory. Energies were also determined at G3MP2, G3MP2B3, G4MP2, and CBS-QB3 levels of theory. Intrinsic reaction coordinate (IRC) calculations were performed to characterize the transition states on the potential energy surface. Thermodynamic properties (ΔE, ΔH, and ΔG), activation energies, enthalpies, and Gibbs free energies of activation were also calculated for each reaction investigated. All pathways yield an initial tetrahedral intermediate and an intermediate in the last step that dissociates to products via a 1,3-proton shift. At the G3MP2 level of theory, deamination with OH(-) was found to have an activation energy barrier of 155 kJ mol(-1) compared to 187 kJ mol(-1) for the reaction with H(2)O and 243 kJ mol(-1) for GuaH(+) with H(2)O. The lowest overall activation energy, 144 kJ mol(-1) at the G3MP2 level, was obtained for the deamination of guanine with H(2)O/OH(-). Due to a lack of experimental results for guanine deamination, a comparison is made with those of cytosine, whose deamination reaction parallels that of guanine.