A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development.

Peptidoglycan is a carbohydrate with a cross-linked structure that protects the cytoplasmic membrane of bacterial cells from damage. The mechanism of peptidoglycan biosynthesis involves the main synthesizing enzyme glycosyltransferase MurG, which is known as a potential target for antibiotic therapy. Many MurG inhibitors have been recognized as MurG targets, but high toxicity and drug-resistant Escherichia coli strains remain the most important problems for further development. In addition, the discovery of selective MurG inhibitors has been limited to the synthesis of peptidoglycan-mimicking compounds. The present study employed drug discovery, such as virtual screening using molecular docking, drug likeness ADMET proprieties predictions, and molecular dynamics (MD) simulation, to identify potential natural products (NPs) for Escherichia coli. We conducted a screening of 30,926 NPs from the NPASS database. Subsequently, 20 of these compounds successfully passed the potency, pharmacokinetic, ADMET screening assays, and their validation was further confirmed through molecular docking. The best three hits and the standard were chosen for further MD simulations up to 400 ns and energy calculations to investigate the stability of the NPs-MurG complexes. The analyses of MD simulations and total binding energies suggested the higher stability of NPC272174. The potential compounds can be further explored in vivo and in vitro for promising novel antibacterial drug discovery.

Identification of Potent Acetylcholinesterase Inhibitors as New Candidates for Alzheimer Disease via Virtual Screening, Molecular Docking, Dynamic Simulation, and Molecular Mechanics-Poisson-Boltzmann Surface Area Calculations.

Huperzine A (HUP) plays a crucial role in Alzheimer's therapy by enhancing cognitive function through increased cholinergic activity as a reversible acetylcholinesterase (AChE) inhibitor. Despite some limitations being seen in AChE inhibitors, ongoing research remains dedicated to finding innovative and more effective treatments for Alzheimer's disease. To achieve the goal of the discovery of potential HUP analogues with improved physicochemical properties, less toxic properties, and high biological activity, many in silico methods were applied. Based on the acetylcholinesterase-ligand complex, an e-pharmacophore model was developed. Subsequently, a virtual screening involving a collection of 1762 natural compounds, sourced from the PubChem database, was performed. This screening yielded 131 compounds that exhibited compatibility with the established pharmacophoric hypothesis. These selected ligands were then subjected to molecular docking within the active site of the 4EY5 receptor. As a result, we identified four compounds that displayed remarkable docking scores and exhibited low free binding energy to the target. These top four compounds, CID_162895946, CID_44461278, CID_44285285, and CID_81108419, were submitted to ADMET prediction and molecular dynamic simulations, yielding encouraging findings in terms of their pharmacokinetic characteristics and stability. Finally, the molecular dynamic simulation, cross-dynamic correlation matrix, free energy landscape, and MM-PBSA calculations demonstrated that two ligands from the selected ligands formed very resilient complexes with the enzyme acetylcholinesterase, with significant binding affinity. Therefore, these two compounds are recommended for further experimental research as possible (AChE) inhibitors.

Rational Design of New Small Derivatives of 2,2'-Bithiophene as Hole Transport Material for Perovskite Solar Cells.

Using Density Functional Theory (DFT) and Time Dependent DFT (TD-DFT) methods, this inquiry theoretically examines seven novel hole-transport materials (HTMs) namely DFBT1, DFBT2, DFBT3, DFBT4, DFBT5, DFBT6, and DFBT7 based on the 2,2'bithiophene core for future use as HTMs for perovskite solar cells (PSCs). The model molecule has been modified through substituting the end groups situated on the diphenylamine moieties with a tow acceptor bridged by thiophene, this modification was performed to test the impact of the π-bridge and acceptor on the electronic, photophysical, and photovoltaic properties of the newly created molecules. DFBT1 - DFBT7 displayed a lower band gap (1.49 eV to 2.69 eV) than the model molecule (3.63 eV). Additionally, the newly engineered molecules presented a greater λmax ranging from 393.07 nm to 541.02 nm in dimethylformamide solvent, as compared to the model molecule (380.61 nm). The PCEs of all newly designed molecules (22.42% to 29.21%) were high compared with the reference molecule (19.62%). Thus, this study showed that all seven newly small molecules were excellent candidates for a novel PSC.

Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations.

A set of 5-(substituted benzylidene) thiazolidine-2,4-dione derivatives was explored to study the main structural requirement for the design of protein tyrosine phosphatase 1B (PTP1B) inhibitors. Utilizing multiple linear regression (MLR) analysis, we constructed a robust quantitative structure-activity relationship (QSAR) model to predict inhibitory activity, resulting in a noteworthy correlation coefficient (R2) of 0.942. Rigorous cross-validation using the leave-one-out (LOO) technique and statistical parameter calculations affirmed the model's reliability, with the QSAR analysis revealing 10 distinct structural patterns influencing PTP1B inhibitory activity. Compound 7e(ref) emerged as the optimal scaffold for drug design. Seven new PTP1B inhibitors were designed based on the QSAR model, followed by molecular docking studies to predict interactions and identify structural features. Pharmacokinetics properties were assessed through drug-likeness and ADMET studies. After that density functional theory (DFT) was conducted to assess the stability and reactivity of potential diabetes mellitus drug candidates. The subsequent dynamic simulation phase provided additional insights into stability and interactions dynamics of the top-ranked compound 11c. This comprehensive approach enhances our understanding of potential drug candidates for treating diabetes mellitus.

Integrative Approach for Designing Novel Triazole Derivatives as α-Glucosidase Inhibitors: QSAR, Molecular Docking, ADMET, and Molecular Dynamics Investigations.

In response to the increasing prevalence of diabetes mellitus and the limitations associated with the current treatments, there is a growing need to develop novel medications for this disease. This study is focused on creating new compounds that exhibit a strong inhibition of alpha-glucosidase, which is a pivotal enzyme in diabetes control. A set of 33 triazole derivatives underwent an extensive QSAR analysis, aiming to identify the key factors influencing their inhibitory activity against α-glucosidase. Using the multiple linear regression (MLR) model, seven promising compounds were designed as potential drugs. Molecular docking and dynamics simulations were employed to shed light on the mode of interaction between the ligands and the target, and the stability of the obtained complexes. Furthermore, the pharmacokinetic properties of the designed compounds were assessed to predict their behavior in the human body. The binding free energy was also calculated using MMGBSA method and revealed favorable thermodynamic properties. The results highlighted three novel compounds with high biological activity, strong binding affinity to the target enzyme, and suitability for oral administration. These results offer interesting prospects for the development of effective and well-tolerated medications against diabetes mellitus.

Design of new molecules against cervical cancer using DFT, theoretical spectroscopy, 2D/3D-QSAR, molecular docking, pharmacophore and ADMET investigations.

Cervical cancer is a major health problem of women. Hormone therapy, via aromatase inhibition, has been proposed as a promising way of blocking estrogen production as well as treating the progression of estrogen-dependent cancer. To overcome the challenging complexities of costly drug design, in-silico strategy, integrating Structure-Based Drug Design (SBDD) and Ligand-Based Drug Design (LBDD), was applied to large representative databases of 39 quinazoline and thioquinazolinone compound derivatives. Quantum chemical and physicochemical descriptors have been investigated using density functional theory (DFT) and MM2 force fields, respectively, to develop 2D-QSAR models, while CoMSIA and CoMFA descriptors were used to build 3D-QSAR models. The robustness and predictive power of the reliable models were verified, via several validation methods, leading to the design of 6 new drug-candidates. Afterwards, 2 ligands were carefully selected using virtual screening methods, taking into account the applicability domain, synthetic accessibility, and Lipinski's criteria. Molecular docking and pharmacophore modelling studies were performed to examine potential interactions with aromatase (PDB ID: 3EQM). Finally, the ADMET properties were investigated in order to select potential drug-candidates against cervical cancer for experimental in vitro and in vivo testing.

Insights into the inhibitory potential of novel hydrazinyl thiazole-linked indenoquinoxaline against alpha-amylase: a comprehensive QSAR, pharmacokinetic, and molecular modeling study.

The rising prevalence of diabetes necessitates the development of novel drugs, especially given the side effects associated with current medications like Acarbose and Voglibose. A series of 36 Hydrazinyl thiazole-linked indenoquinoxaline derivatives with notable activity against alpha-amylase were studied. To create a molecular model predicting alpha-amylase activity, a QSAR study was performed on these compounds. Molecular descriptors were calculated using Chem3D and Gaussian software and then correlated with their IC50 biological activities to form a dataset. This model data was refined using PCA and modeled with MLR. The model's performance was statistically verified (R2 =0.800; Radj2 = 0.767; Rcv2 = 0.651) and its applicability domain was defined. It was predicted to possess high predictive power (Rtest2  = 0.872). Based on this, new compounds were proposed, and their activities were predicted using the developed model. Additionally, their binding ability to the biological target was studied through molecular docking and dynamics. Their pharmacokinetics were also evaluated using ADMET predictions. Two designed compounds named AE and AB emerged as particularly promising, displaying properties that suggest substantial therapeutic potential and they can form stable complexes into the binding pocket of alpha-amylase enzyme.Communicated by Ramaswamy H. Sarma.

Genotoxic effects and mitosis aberrations of chromium (VI) on root cells of Vicia faba and its molecular docking analysis.

Like other heavy metals, Cr (VI) is a powerful carcinogen and mutagen agent. Its toxic effects on plants are well considered. In order to elucidate its adverse effects, the present work aims to study the mitosis aberrations of Cr (VI) on the Vicia faba root-cells and its molecular docking analysis to understand the genotoxicity mechanisms. In-vivo, Vicia faba plants were exposed to 50 and 100 µM Cr (VI) for 48 h. In-silico, molecular docking and molecular dynamics simulation were used to study the interactions between dichromate and tubulin tyrosine ligase T2R-TTL (PDBID: 5XIW) with reference to Colchicine (microtubule inhibitor). According to our results, Cr (VI) affects growth and cell division and also induces many mitosis aberrations such as chromosome sticking, anaphase/telophase bridges, lagging chromosomes and fragmentation during all phases of mitosis. On the one hand, Cr (VI) reduces mitotic index and promotes micronuclei induction. The in-silico results showed that dichromate establishes very strong bonds at the binding site of the tubulin tyrosine ligase T2R-TTL, with a binding affinity of -5.17 Kcal/Mol and an inhibition constant of 163.59 µM. These interactions are similar to those of colchicine with this protein, so dichromate could be a very potent inhibitor of this protein's activity. TTL plays a fundamental role in the tyrosination/detyrosination of tubulin, which is crucial to the regulation of the microtubule cytoskeleton. Its inhibition leads to the appearance of many morphogenic abnormalities such as mitosis aberrations. In conclusion, our data confirm the highest genotoxicity effects of Cr (VI) on Vicia faba root-cells.

Design of new small molecules derived from indolin-2-one as potent TRKs inhibitors using a computer-aided drug design approach.

Tropomyosin receptor kinase (TRKs) enzymes are responsible for cancers associated with the neurotrophic tyrosine kinase receptor gene fusion and are identified as effective targets for anticancer drug discovery. A series of small-molecule indolin-2-one derivatives showed remarkable biological activity against TRKs enzymatic activity. These small molecules could have an excellent profile for pharmaceutical application in the treatment of cancers caused by TRKs activity. The aim of this study is to modify the structure of these molecules to obtain new molecules with improved TRK inhibitory activity and pharmacokinetic properties favorable to the design of new drugs. Based on these series, we carried out a 3D-QSAR study. As a result, robust and reliable CoMFA and CoMSIA models are developed and applied to the design of 11 new molecules. These new molecules have a biological activity superior to the most active molecule in the starting series. The eleven designed molecules are screened using drug-likeness, ADMET proprieties, molecular docking, and MM-GBSA filters. The results of this screening identified the T1, T3, and T4 molecules as the best candidates for strong inhibition of TRKs enzymatic activity. In addition, molecular dynamics simulations are performed for TRK free and complexed with ligands T1, T3, and T4 to evaluate the stability of ligand-protein complexes over the simulation time. On the other hand, we proposed experimental synthesis routes for these newly designed molecules. Finally, the designed molecules T1, T2, and T3 have great potential to become reliable candidates for the conception of new drug inhibitors of TRKs.Communicated by Ramaswamy H. Sarma.

Ligand-Based Design of Novel Quinoline Derivatives as Potential Anticancer Agents: An In-Silico Virtual Screening Approach.

In this study, using the Comparative Molecular Field Analysis (CoMFA) approach, the structure-activity relationship of 33 small quinoline-based compounds with biological anti-gastric cancer activity in vitro was analyzed in 3D space. Once the 3D geometric and energy structure of the target chemical library has been optimized and their steric and electrostatic molecular field descriptions computed, the ideal 3D-QSAR model is generated and matched using the Partial Least Squares regression (PLS) algorithm. The accuracy, statistical precision, and predictive power of the developed 3D-QSAR model were confirmed by a range of internal and external validations, which were interpreted by robust correlation coefficients (RTrain2=0.931; Qcv2=0.625; RTest2=0.875). After carefully analyzing the contour maps produced by the trained 3D-QSAR model, it was discovered that certain structural characteristics are beneficial for enhancing the anti-gastric cancer properties of Quinoline derivatives. Based on this information, a total of five new quinoline compounds were developed, with their biological activity improved and their drug-like bioavailability measured using POM calculations. To further explore the potential of these compounds, molecular docking and molecular dynamics simulations were performed in an aqueous environment for 100 nanoseconds, specifically targeting serine/threonine protein kinase. Overall, the new findings of this study can serve as a starting point for further experiments with a view to the identification and design of a potential next-generation drug for target therapy against cancer.

Design, synthesis, In-vitro, In-silico and DFT studies of novel functionalized isoxazoles as antibacterial and antioxidant agents.

A series of new isoxazolederivatives incorporating the sulfonate ester function has been synthesized from 2-benzylidenebenzofuran-3(2 H)-one, known as aurone. The synthesis of the target compounds was carried out following an efficient methodology that allows access to the desired products in a reproducible way and with good yield. The structures of the synthesized compounds were established using NMR (1H and 13C) spectroscopy and mass spectrometry. A theoretical study was performed to optimize the geometrical structures and to calculate the structural and electronic parameters of the synthesized compounds. The calculations were also carried out to understand the influence and the effect of substitutions on the chemical reactivity of the studied compounds. The synthesized isoxazoles were screened for their antioxidant and antibacterial activities. The findings demonstrate that the studied compounds exhibit good to moderate antibacterial activity against the tested bacteria (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli). Moreover, a number of the tested isoxazole derivatives exhibit high effectiveness against DPPH free radicals. Besides that, molecular docking studies were carried out to predict binding affinity and identify the most likely binding interactions between the active molecules and the target microorganisms' proteins. A 100 ns molecular dynamics study was then conducted to examine the dynamic behavior and stability of the highly potent isoxazole 4e in complex with the target bacterial proteins. Finally, the ADMET analyses suggest that all the synthesized isoxazoles have good pharmacokinetic profiles and non-toxicity and non-carcinogenicity in biological systems.

Molecular docking, drug-likeness and DFT study of some modified tetrahydrocurcumins as potential anticancer agents.

The present study utilized molecular docking and density functional theory (DFT) approaches, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties to investigate the binding interactions, reactivity, stability, and drug-likeness of curcumin (1), tetrahydrocurcumin (2), and tetrahydrocurcumin derivatives (3-6) as potential anti-cancer agents. MGL (Molecular Graphic Laboratory) and Discovery Studio Visualizer (DSV) software employed for docking studies. Pharmacokinetic and pharmacodynamic (ADME-Tox) analyses were conducted using SwissADME and pKCSM web servers. Total Electron Density (TED) measurements identified molecular adsorption sites, considering various factors, including quantum chemical characteristics, to assess compound effectiveness using DFT method implanted in the Gaussian software. The binding energy (Eb) from docking simulations was used to evaluate inhibitory potential. ADMET analysis suggested favorable oral bioavailability and pharmacokinetics for all studied substances, excluding compound 4. DFT and docking investigations highlighted compounds 1, 2, and 6 as optimal scaffolds for drug design based on in silico screening tests.

Structure-based virtual screening, ADMET analysis, and molecular dynamics simulation of Moroccan natural compounds as candidates for the SARS-CoV-2 inhibitors.

The lack of treatments and vaccines effective against SARS-CoV-2 has forced us to explore natural compounds that could potentially inhibit this virus. Additionally, Morocco is renowned for its rich plant diversity and traditional medicinal uses, which inspires us to leverage our cultural heritage and the abundance of natural resources in our country for therapeutic purposes. In this study, an extensive investigation was conducted to gather a collection of phytoconstituents extracted from Moroccan plants, aiming to evaluate their ability to inhibit the proliferation of the SARS-CoV-2 virus. Molecular docking of the studied compounds was performed at the active sites of the main protease (6lu7) and spike (6m0j) proteins to assess their binding affinity to these target proteins. Compounds exhibiting high affinity to the proteins underwent further evaluation based on Lipinski's rule and ADME-Tox analysis to gain insights into their oral bioavailability and safety. The results revealed that the two compounds demonstrated strong binding affinity to the target proteins, making them potential candidates for oral antiviral drugs against SARS-CoV-2. The molecular dynamics results from this computational analysis supported the overall stability of the resulting complex.

Chromone-isoxazole hybrids molecules: synthesis, spectroscopic, MEDT, ELF, antibacterial, ADME-Tox, molecular docking and MD simulation investigations.

A mechanistic study was performed within the molecular electron density theory at the B3LYP/6-311G (d,p) computational level to explain the regioselectivity observed. An electron localization function analysis was also performed, and the results confirm the zwitterionic-type (zw-type) mechanism of the cycloaddition reactions between nitrile oxide and alkylated 4H-chromene-2-carboxylate derivatives and shed more light on the obtained regioselectivity experimentally. In silico studies on the pharmacokinetics, ADME and toxicity tests of the compounds were also performed, and it was projected that compounds 5a, 5b, 5c and 5d are pharmacokinetic and have favorable ADME profiles. Moreover, docking and molecular dynamics investigations were conducted to evaluate the interactions, orientation and conformation of the target compounds on the active sites of four distinct enzymes. The results of this investigation showed that two compounds, 5a and 5c, interacted effectively with the S. aureus active site while maintaining acceptable binding energy.Communicated by Ramaswamy H. Sarma.

Identification of novel curcumin derivatives against pancreatic cancer: a comprehensive approach integrating 3D-QSAR pharmacophore modeling, virtual screening, and molecular dynamics simulations.

Pancreatic cancer, known as the "silent killer," poses a daunting challenge in cancer therapy. The dysregulation of the PI3Kα signaling pathway in pancreatic cancer has attracted considerable interest as a promising target for therapeutic intervention. In this regard, the use of curcumin derivatives as inhibitors of PI3Kα has emerged, providing a novel and promising avenue for developing effective treatments for this devastating disease. Computational approaches were employed to explore this potential and investigate 58 curcumin derivatives with cytotoxic activity against the Panc-1 cell line. Our approach involved ligand-based pharmacophore modeling and atom-based 3D-QSAR analysis. The resulting QSAR model derived from the best-fitted pharmacophore hypothesis (AAHRR_1) demonstrated remarkable performance with high correlation coefficients (R2) of 0.990 for the training set and 0.977 for the test set. The cross-validation coefficient (Q2) of 0.971 also validated the model's predictive power. Tropsha's recommended criteria, including the Y-randomization test, were employed to ensure its reliability. Furthermore, an enrichment study was conducted to evaluate the model's performance in identifying active compounds. AAHRR_1 was used to screen a curated PubChem database of curcumin-related compounds. Two molecules (CID156189304 and CID154728220) exhibited promising pharmacokinetic properties and higher docking scores than Alpelisib, warranting further investigation. Extensive molecular dynamics simulations provided crucial insights into the conformational dynamics within the binding site, validating their stability and behavior. These findings contribute to our understanding of the potential therapeutic effectiveness of these compounds as PI3Kα inhibitors in pancreatic cancer.Communicated by Ramaswamy H. Sarma.

Synthesis, biological evaluation and molecular modelling of 3-Formyl-6-isopropylchromone derived thiosemicarbazones as α-glucosidase inhibitors.

Type-2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders in the world and over the past three decades its incidence has increased drastically. α-Glucosidase inhibitors are used to control the hyperglycemic affect of T2DM. Herein, we report the synthesis, α-glucosidase inhibition, structure activity relationship, pharmacokinetics and docking analysis of various novel chromone based thiosemicarbazones 3(a-r). The derivatives displayed potent activity against α-glucosidase with IC50 in range of 0.11 ± 0.01-79.37 ± 0.71 µM. Among all the synthesized compounds, 3a (IC50 = 0.17 ± 0.026 µM), 3 g (IC50 = 0.11 ± 0.01 µM), 3n (IC50 = 0.55 ± 0.02 µM), and 3p (IC50 = 0.43 ± 0.025 µM) displayed higher inhibitory activity as compared to the standard, acarbose. Moreover, we have developed a statistically significant 2D-QSAR model (R2tr:0.9693; F: 50.4647 and Q2LOO:0.9190), which can be used in future to further design potent thiosemicarbazones as inhibitors of α-glucosidase.

The anti-SARS-CoV-2 activity of novel 9, 10-dihydrophenanthrene derivatives: an insight into molecular docking, ADMET analysis, and molecular dynamics simulation.

Originating in Wuhan, the COVID-19 pandemic wave has had a profound impact on the global healthcare system. In this study, we used a 2D QSAR technique, ADMET analysis, molecular docking, and dynamic simulations to sort and evaluate the performance of thirty-nine bioactive analogues of 9,10-dihydrophenanthrene. The primary goal of the study is to use computational approaches to create a greater variety of structural references for the creation of more potent SARS-CoV-2 3Clpro inhibitors. This strategy is to speed up the process of finding active chemicals. Molecular descriptors were calculated using 'PaDEL' and 'ChemDes' software, and then redundant and non-significant descriptors were eliminated by a module in 'QSARINS ver. 2.2.2'. Subsequently, two statistically robust QSAR models were developed by applying multiple linear regression (MLR) methods. The correlation coefficients obtained by the two models are 0.89 and 0.82, respectively. These models were then subjected to internal and external validation tests, Y-randomization, and applicability domain analysis. The best model developed is applied to designate new molecules with good inhibitory activity values against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). We also examined various pharmacokinetic properties using ADMET analysis. Then, through molecular docking simulations, we used the crystal structure of the main protease of SARS-CoV-2 (3CLpro/Mpro) in a complex with the covalent inhibitor "Narlaprevir" (PDB ID: 7JYC). We also supported our molecular docking predictions with an extended molecular dynamics simulation of a docked ligand-protein complex. We hope that the results obtained in this study can be used as good anti-SARS-CoV-2 inhibitors.

Repositioning Cannabinoids and Terpenes as Novel EGFR-TKIs Candidates for Targeted Therapy Against Cancer: A virtual screening model using CADD and biophysical simulations.

This study examines the potential of Cannabis sativa L. plants to be repurposed as therapeutic agents for cancer treatment through designing of hybrid Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). A set of 50 phytochemicals was taken from Cannabinoids and Terpenes and subjected for screening using Semi-flexible and Flexible Molecular Docking methods, MM-GBSA free binding energy computations, and pharmacokinetic/pharmacodynamic (ADME-Tox) predictions. Nine promising phytochemicals, Cannabidiolic acid (CBDA), Cannabidiol (CBD), Tetrahydrocannabivarin (THCV), Dronabinol (Δ-9-THC), Delta-8-Tetrahydrocannabinol (Δ-8-THC), Cannabicyclol (CBL), Delta9-tetrahydrocannabinolic acid (THCA), Beta-Caryophyllene (BCP), and Gamma-Elemene (γ-Ele) were identified as potential EGFR-TKIs natural product candidates for cancer therapy. To further validate these findings, a set of Molecular Dynamics simulations were conducted over a 200 ns trajectory. This hybrid early drug discovery screening strategy has the potential to yield a new generation of EGFR-TKIs based on natural cannabis products, suitable for cancer therapy. In addition, the application of this computational strategy in the virtual screening of both natural and synthetic chemical libraries could support the discovery of a wide range of lead drug agents to address numerous diseases.

In silico and POM analysis for potential antimicrobial agents of thymidine analogs by using molecular docking, molecular dynamics and ADMET profiling.

Nucleoside analogs are an important, well-established class of clinically useful medicinal agents that exhibit potent antimicrobial activity. Thus, we designed to explore the synthesis and spectral characterization of 5'-O-(myristoyl)thymidine esters (2-6) for in vitro antimicrobial, molecular docking, molecular dynamics, SAR, and POM analyses. An unimolar myristoylation of thymidine under controlled conditions furnished the 5'-O-(myristoyl)thymidine and it was further converted into four 3'-O-(acyl)-5'-O-(myristoyl)thymidine analogs. The chemical structures of the synthesized analogs were ascertained by analyzing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests along with PASS, prediction indicated expectant antibacterial functionality of these thymidine esters compared to the antifungal activities. In support of this observation, their molecular docking studies have been performed against lanosterol 14α-demethylase (CYP51A1) and Aspergillus flavus (1R51) and significant binding affinities and non-bonding interactions were observed. The stability of the protein-ligand complexes was monitored by a 100 ns MD simulation and found the stable conformation and binding mode in a stimulating environment of thymidine esters. Pharmacokinetic predictions were studied to assess their ADMET properties and showed promising results in silico. SAR investigation indicated that acyl chains, lauroyl (C-12) and myristoyl (C-14), combined with deoxyribose, were most effective against the tested bacterial and fungal pathogens. The POM analyses provide the structural features responsible for their combined antibacterial/antifungal activity and provide guidelines for further modifications, with the aim of improving each activity and selectivity of designed drugs targeting potentially drug-resistant microorganisms. It also opens avenues for the development of newer antimicrobial agents targeting bacterial and fungal pathogens.

A novel series of 5´-O-(myristoyl)thymidine derivatives were synthesized and characterized by FTIR, ¹H-NMR, 2D-NMR, ¹³C-NMR, mass and physicochemical studies.In vitro antimicrobial susceptibility revealed that alkyl chain and aromatic substituents can improve the antimicrobial efficacy of the thymidine structure which was also supported by PASS enumeration.Molecular docking study against lanosterol 14α-demethylase (CYP51A1) and Aspergillus flavus (1R51) exhibited a promising binding score and interaction in the catalytic active site.A 100ns MD simulation revealed the stable conformation and binding pattern in a stimulating environment of thymidine derivatives.ADMET analysis revealed that most of the compounds are non-toxic and most of them have an inhibitory property to the CYP1A2 and CYP3A4In silico and POM analyses provide substantial ideas about the structural features responsible for their combined antibacterial/antifungal agents and provide guidelines for further modifications.

In vitro and in silico analysis for elucidation of antioxidant potential of Djiboutian Avicennia Marina (Forsk.) Vierh. phytochemicals.

The present work aims to study the phytochemical composition, the antioxidant capacity of the crude extracts, and the fraction of extract giving the best antioxidant activity of Avicennia marina. The leaves contain high TFC compared to other parts of the plant, whereas fruits have the highest amount of TPC. Fat-soluble pigments are strongly present in the leaves of Avicennia marina i.e. ß-carotene, lycopene, chlorophyll a, and chlorophyll b. The crude methanolic flower extracts showed strong DPPH and ABTS radical scavenging activity with IC50 values of 0.30 and 0.33 mg/mL respectively compared to the leaf and stem methanolic extracts for the DPPH and ABTS models with a value IC50 greater than 1 mg/mL. The crude fruit extract shows good activity with the ABTS model, unlike the DPPH model whose IC50 values are 0.95 and 0.38 mg/mL, respectively. Fractionation improved the antioxidant effect of crude flower extract. The ethyl acetate fraction exhibits the best antioxidant activity for both DPPH and ABTS methods with IC50 values of 0.125 and 0.16 mg/mL. The HR-LCMS/MS led to the identification of 13 compounds: 6 flavonoids and 7 iridoid glycoside compounds in the different parts of the plant. A bioinformatics study was performed to evaluate the antioxidant activity of the three major Iridoid glycosides towards the target protein Catalase compound II through free binding energy. Out of these three iridoid glycosides, compound C10 does not represent any toxicity, unlike C8 and C9 which showed an irritancy effect. Furthermore, molecular dynamics shows good stability of the C10-2CAG complex. HighlightsExtraction and fractionation of different part (leaf, stem, flower and fruit) of Avicennia marina.Botanical description and phytochemical analysis of crude extract methanolic. Investigation by HR-LCMS characterization of polyphenols and iridoid glycosides.Evaluation the antioxidant activity of crudes extracts methanolics by two methods in vitro DPPH and ABTS.Antioxidant activity of the fraction of the crude flower extracts presenting the best biological response.Evaluate the contribution of three major compounds 2'-Cinnamoylmussaenosidic acid, 10-O-[E-Cinnamoyl]-geniposidic acid and 10-O-[(E)-p-Coumaroyl]-geniposidic acid in the ethyl acetate fraction on the antioxidant activity through docking and dynamic molecular.Communicated by Ramaswamy H. Sarma.