Потенциальные противомикробные агенты на основе тимидина с помощью расчетов In Silico DFT

Modification of the hydroxyl (–OH) group of thymidine by acylation may cause changes in the antimicrobial and anticancer properties of thymidine which is investigated in this study. The current study is concentrated towards the in silico computational study of different in silico and bioactivity investigations. We relate the optimization of thymidine and its acylated analogs by applying density functional theory (DFT) with B 3LYP/3–21G level theory to demonstrate their thermal, frontier molecular orbital, the density of states (DOS) and molecular electrostatic potential (MESP) properties. All the analogs were found with enriched score than their parent atom which indicates the theoretical stability of these compounds. To deeply realize these observations molecular docking studies have been performed against human PARP1 (E.coli-BL21, PDB: 4ZZZ) and remarkable binding energies and non-covalent interactions were observed. Bioactivity data exhibited that compounds consisted of standard values in predicted cases. Moreover, toxicity data showed a safer level of the score for all studied thymidine analogs. This work demonstrates that potential thymidine analogs bind to bacterial pathogens for circumventing their activities and opens avenues for the development of newer drug candidates that can target bacterial and fungal pathogensМодификация гидроксильной (–OH) группы тимидина путем ацилирования может вызвать изменения в антимикробных и противоопухолевых свойствах тимидина, которые исследуются в данной работе. Текущее исследование сосредоточено на вычислительном изучении in silico различных исследований in silico и биоактивности. Мы связываем оптимизацию тимидина и его ацилированных аналогов с применением теории функционала плотности (DFT) с теорией уровней B 3LYP/3–21G, чтобы продемонстрировать их тепловые свойства, пограничную молекулярную орбиталь, плотность состояний (DOS) и молекулярный электростатический потенциал (MESP). Все аналоги были обнаружены с показателем, превышающим их исходный атом, что указывает на теоретическую стабильность этих соединений. Чтобы глубже осознать эти наблюдения, были проведены исследования молекулярного докинга против PARP1 человека (E.coli-BL21, PDB: 4ZZZ) и обнаружены значительные энергии связи и нековалентные взаимодействия. Данные о биологической активности показали, что соединения в прогнозируемых случаях соответствовали стандартным значениям. Более того, данные о токсичности показали более безопасный уровень оценки для всех изученных аналогов тимидина. Эта работа демонстрирует, что потенциальные аналоги тимидина связываются с бактериальными патогенами, чтобы обойти их активность, и открывает возможности для разработки новых лекарственных препаратов-кандидатов, которые могут воздействовать на бактериальные и грибковые патоген

Исследования по прогнозированию проходимости, ADMET и молекулярному докингу некоторых производных маннопиранозида против полимеразы NS 5B HCV

Several carbohydrate-based medications are now being used to treat a variety of human ailments all around the world. Therefore, we concentrated on computational investigations of previously synthesized methyl α-D‑mannopyranoside (MDM) derivatives. To determine the structural and thermodynamical properties of the modified derivatives, a quantum chemical research was conducted using Gaussian09 employing density functional theory (DFT). Molecular electrostatic potential (MEP) calculation has performed to calculate their possible electrophilic and nucleophilic attack. The binding energy and binding strategies of certain viral proteins from the Hepatitis C virus (2IJN, 3MWV, and 3FKQ) were investigated using molecular docking simulations, and adequate binding affinity was discovered. ADMET calculations predict the improved pharmacokinetic properties with better drug-likeness profile of all MDM derivatives. Finally, these compounds can be described as molecules with high antiviral/antimicrobial potential that have been modified in terms of their structural side chains in α-D‑mannopyranoside sequenceНесколько препаратов на основе углеводов в настоящее время используются для лечения различных заболеваний человека по всему миру. Поэтому мы сосредоточились на вычислительных исследованиях ранее синтезированных производных метил-α-D‑маннопиранозида (MDM). Чтобы определить структурные и термодинамические свойства модифицированных производных, было проведено квантово-химическое исследование с применением Gaussian 09 и с использованием теории функционала плотности (DFT). Был проведен расчет молекулярного электростатического потенциала (MEP) для расчета их возможной электрофильной и нуклеофильной атаки. Энергия связывания и стратегии связывания определенных вирусных белков вируса гепатита С (2IJN, 3MWV и 3FKQ) были исследованы с использованием моделирования молекулярного докинга, и была обнаружена адекватная аффинность связывания. Расчеты ADMET предсказывают улучшенные фармакокинетические свойства с лучшим профилем лекарственного подобия всех производных MDM. Наконец, эти соединения могут быть описаны как молекулы с высоким противовирусным/антимикробным потенциалом, которые были модифицированы с точки зрения их структурных боковых цепей в последовательности α-D‑маннопиранозид

Simple and rapid synthesis of some nucleoside derivatives: structural and spectral characterization

In our present investigation a new series of nucleoside derivatives (2-13) were synthesized from uridine (1) via only two step reactions by direct acylation method. Firstly, uridine (1) was treated with 4-t-butylbenzoyl chloride in pyridine at -5ºC and afforded the 5´-O-(4-t-butylbenzoyl)uridine derivative (2) in an excellent yield. In order to obtain newer products, the 5´-O-uridine derivative was further transformed to a series of 2´,3´-di-O-acyl derivatives (2-13) containing a wide variety of functionalities in a single molecular framework. The yields of the compounds were more than 80%. The synthesized titled compounds were characterized by their physical properties, FTIR (Fourier transform infrared spectroscopy), 1H-NMR (Nuclear magnetic resonance) spectroscopy and elemental analysis

Simple and rapid synthesis of some nucleoside derivatives: structural and spectral characterization

In our present investigation a new series of nucleoside derivatives (2-13) were synthesized from uridine (1) via only two step reactions by direct acylation method. Firstly, uridine (1) was treated with 4-t-butylbenzoyl chloride in pyridine at -5ºC and afforded the 5´-O-(4-tbutylbenzoyl)uridine derivative (2) in an excellent yield. In order to obtain newer products, the 5´-O-uridine derivative was further transformed to a series of 2´,3´-di-O-acyl derivatives (2-13) containing a wide variety of functionalities in a single molecular framework. The yields of the compounds were more than 80%. The synthesized titled compounds were characterized by their physical properties, FTIR (Fourier transform infrared spectroscopy), 1H-NMR (Nuclear magnetic resonance) spectroscopy and elemental analysis

Pharmacoinformatics and Breed-Based De Novo Hybridization Studies to Develop New Neuraminidase Inhibitors as Potential Anti-Influenza Agents

Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected cell to host cells. As such, neuraminidase has emerged as a pivotal target for mitigating influenza and its associated complications. Here, we apply a de novo hybridization approach based on a breed-centric methodology to elucidate novel neuraminidase inhibitors. The breed technique amalgamates established ligand frameworks with the shared target, neuraminidase, resulting in innovative inhibitor constructs. Molecular docking analysis revealed that the seven synthesized breed molecules (designated Breeds 1–7) formed more robust complexes with the neuraminidase receptor than conventional clinical neuraminidase inhibitors such as zanamivir, oseltamivir, and peramivir. Pharmacokinetic evaluations of the seven breed molecules (Breeds 1–7) demonstrated favorable bioavailability and optimal permeability, all falling within the specified parameters for human application. Molecular dynamics simulations spanning 100 nanoseconds corroborated the stability of these breed molecules within the active site of neuraminidase, shedding light on their structural dynamics. Binding energy assessments, which were conducted through MM-PBSA analysis, substantiated the enduring complexes formed by the seven types of molecules and the neuraminidase receptor. Last, the investigation employed a reaction-based enumeration technique to ascertain the synthetic pathways for the synthesis of the seven breed molecules

Synthesis, antimicrobial activity, molecular docking, molecular dynamics simulation, and ADMET properties of the mannopyranoside derivatives as antimicrobial agents

Multiple diseases are treated with carbohydrate-based medicinal products worldwide. Direct regioselective acylation of methyl α-D-mannopyranoside (MDMP) derivatives 2-6 afforded from the 6-O-butyryl derivative. This isolated 6-O-derivative was converted to 2,3,4-tri-O-acyl derivatives, and the resulting compounds were analyzed using FTIR, 1H-NMR, 13C-NMR, and elemental analysis. The acylated derivatives showed moderate to good antimicrobial activity. Cytotoxicity assessment indicated that compound 2 had the lowest toxicity. A SAR study demonstrated that lauroyl and myristoyl acyl chains combined with mannopyranose were particularly effective against bacteria. In this context, molecular docking analysis demonstrated crucial interactions involved in assessing the binding affinity of ligands 1-6 for the active sites of Escherichia coli (4XO8) and Aspergillus flavus (1R51). A 100-ns molecular dynamics simulation showed that all the compounds were stable at the active site of protein 1R51. In silico ADMET prediction revealed greater drug similarity for MDMP derivatives. The results of this investigation may help create MDMP derivative-based multidrug-resistant antimicrobial agents.Highlights Methyl α-D-mannopyranoside (MDMP) derivatives were designed, and synthesized, and their structures were ascertained via spectral analyses.MDMPs were assessed in vitro to identify potential antibacterial or antifungal potential antimicrobial candidate(s) against human and plant organisms.Molecular docking results revealed significant interactions between compounds 1-6 and the active sites of Escherichia coli (4XO8) and Aspergillus flavus (1R51).A 100 ns molecular dynamic simulation demonstrated that the docked ligand–receptor complex had better dynamic stability, as determined through the RMSD, RMSF, SASA, and Rg profiles.ADMET prediction revealed an improved drug-likeness profile for all MDMP derivatives