Computational Biology and Chemistry最新文献

{"title":"In vitro antioxidant (spectrophotometric/electrochemical) and enzymatic activities of aniline derivative Schiff base: Experimental and computational assessment","authors":"Zakia Messasma ,&nbsp;Djouhra Aggoun ,&nbsp;Mostefa Hani ,&nbsp;Leila Ailane ,&nbsp;Nada Hiba Boukoucha ,&nbsp;Chawki Bensouici ,&nbsp;Yasmina Ouennoughi","doi":"10.1016/j.compbiolchem.2025.108699","DOIUrl":"10.1016/j.compbiolchem.2025.108699","url":null,"abstract":"<div><div>Hereby, the <em>in vitro</em> biological, electrochemical, computational, molecular docking, and <em>in silico</em> ADMET properties of the H₂L ligand have been investigated. The antioxidant potential was evaluated using spectrochemical as well as electrochemical assays. H₂L was found to exhibit intriguing antioxidant capacities in almost several <em>in vitro</em> applications of tests such as DPPH, ABTS, GOR, PRAC, reducing power, CUPRAC, phenanthroline, and the optical properties of silver nanoparticles (SNPs). The H₂L showed scavenging ability against electrochemically generated superoxide anion radical (O₂^{<strong>·−</strong>}) by electrochemical reduction of O₂ quantitated in terms of I %. Furthermore, H₂L was tested for some enzymatic inhibition activities (cholinesterase, tyrosinase, urease, and α-amylase), displaying higher inhibition toward these selected enzymes. A theoretical study was carried out by the density functional (DFT) method (gas phase/B3LYP functional associated with the 6–31G (d,p) basis) for thermodynamic behavior, stability, and reactivity prediction. Then, a docking study was performed using AutoDock and MG-tools programs with the same selected proteins with PDB IDs as follows: 4EY7, 4BDS, 2Y9X, 3LA4, and 2QV4, respectively, to visualize the best docked pose and favorable ligand-protein binding interactions. The <em>in silico</em> results revealed that H₂L exhibited stronger tyrosinase inhibitory activity than kojic acid. Thus, these results showed good agreement with the experimental data obtained from the enzyme-inhibiting assay. Finally, several important physicochemical descriptors were examined through <em>in silico</em> ADMET analysis and additionally processed through <em>in vitro</em> PAMPA-BBB permeability assay. Finally, to identify the optimal combinations with the antioxidant responses and based on the results obtained from the response surface methodology (RSM), optimization analyses were also carried out.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108699"},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methyl 2-(7-hydroxy-3-methyloctyl)-1,3-dimethyl-4-oxocyclohex-2-enecarboxylate as a natural and potent antitubercular lead: An in silico study integrating molecular docking, molecular dynamics, FMO, and DFT analyses","authors":"Fathima Asra ,&nbsp;Kannan Vadivel ,&nbsp;Srikanth Jeyabalan ,&nbsp;Srilekha Chintala ,&nbsp;Naresh Dumala","doi":"10.1016/j.compbiolchem.2025.108691","DOIUrl":"10.1016/j.compbiolchem.2025.108691","url":null,"abstract":"<div><div>The currently marketed antitubercular drugs have limited efficacy with the potential to cause organ toxicity. Thus, there is a need for new drug therapies to combat tuberculosis. Methyl 2-(7-hydroxy-3-methyloctyl)-1,3-dimethyl-4-oxocyclohex-2-enecarboxylate (PE14) and (<em>E</em>)-3,7,11,15-tetramethylhexadec-2-en-1-ol (EA8) are the natural antitubercular lead-like molecules isolated from petroleum ether and ethyl acetate leaf extracts of <em>Ipomea sepiaria,</em> respectively. Extensive research has demonstrated the wide range of health benefits associated with this plant. However, the antitubercular effects of phytocompounds isolated from this species have not been systematically investigated. To evaluate the antitubercular effect of the natural compound, <em>in silico</em> prediction of binding affinity against selected antitubercular target proteins was conducted, and this was compared with co-crystallized ligands as a standard. Additionally, the physicochemical properties, pharmacokinetics, and various toxicity-related parameters were also predicted. Two ligand docking complexes were selected for molecular dynamics simulations to calculate the binding free energy over 250 ns. Moreover, FMO and DFT were also investigated. PE14 complies with RO5 and exhibits suitable ADMET profiles. The molecular docking scores in kcal/mol showed comparatively more potency against antitubercular drug targets compared to the co-crystalized ligand of the target protein as well as EA8. Overall, the strength of interaction between the ligands with their selected target proteins from the molecular docking study, heat change that occurs during the ligand-target interactions from a molecular dynamic simulation study, the electronic reactivity trend was established as STD &gt; PE14 &gt; CIP &gt; EA8 from FMO analysis and other multi-parametric druggability profiles of target proteins suggests that PE14 can be considered as a suitable antitubercular lead-like for the treatment of <em>M. tuberculosis</em>. The results of the current study were closely correlated with those of our previous study on <em>Ipomea sepiaria</em> in the LRP assay. However, necessary <em>in vitro</em> and <em>in vivo</em> studies on the synthesized pure compound must be carried out to participate in a clinical trial, where the <em>in silico</em> results would help expedite the process of drug development.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108691"},"PeriodicalIF":3.1,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognosis models for nasopharyngeal carcinoma recurrences by using tabu search algorithm","authors":"Yara Raslan ,&nbsp;Mushabab Asiri ,&nbsp;Ahmed M. Maklad ,&nbsp;Alaa Fahim","doi":"10.1016/j.compbiolchem.2025.108687","DOIUrl":"10.1016/j.compbiolchem.2025.108687","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Cancer is a significant public health issue that has a global impact. Significant mortality rates have already been observed due to this disease, and more mortalities are expected in the future. In recent times, there has been a growing interest among otolaryngologists and oncologists in the development of appropriate treatment regimens for patients with recurrent nasopharyngeal carcinoma (NPC). The primary objective of these treatment modalities is to extend the lifespan of patients following recurrence and enhance their overall survival and quality of life. For instance, metaheuristic algorithms (MH), a form of soft computing technology, are commonly utilized in healthcare data due to their effectiveness. Furthermore, metaheuristics rely on the evolutionary search principle. They direct the search process to effectively explore the search space in order to find near-optimal solutions for solving global optimization problems. Tabu search (TS) is a method used in optimization problems and falls under metaheuristic techniques. An essential element of TS is its utilization of adaptive memory, which enhances search efficiency by avoiding local optimality and promoting flexibility. Another example is data mining, which is a subset of artificial intelligence that utilizes data to extract meaningful information from previously unknown patterns. It has been increasingly used in healthcare to aid clinical diagnostics and disease prediction. The proposed technique treated data mining problems as combinatorial optimization problems and used metaheuristics to address data mining challenges, such as classification for unknown data and finding association rules for significant patterns. The Tabu Search Classifier Method (TSCM) outlined in this paper primarily utilizes the Tabu Search (TS) algorithm, enhanced with the incorporation of Dynamic Neighborhood Structure (DNHS), which contributes to better discovery of the search space. The TSCM algorithm identifies three rules based on the patients’ data and generates three precise artificial predictive models to determine and categorize individuals who are at risk of recurrent NPC. With each stage of the treatment, additional features become accessible. The first model relies on a primary data set that includes descriptive data. The second model incorporates more features than the first model but does not include the response feature. The third model utilizes all existing features and includes the response feature, which is observed three months after the treatment phase concludes, the third model is considered a post-treatment monitoring. This paper introduces an Artificial Advisory Healthcare System (AAHS) that utilizes these models to accurately predict the occurrence of recurrence during each stage of treatment and after the treatment as a post-treatment monitoring. This prediction enables the adjustment of the treatment plan and the implementation of additional measures in accordance with the system","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108687"},"PeriodicalIF":3.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive breast cancer detection: Leveraging the potential of BN-doped C60 heterofullerene for formaldehyde sensing using DFT theory","authors":"Bharath Kumar Chagaleti ,&nbsp;Arafat Toghan ,&nbsp;Magdi E.A. Zaki ,&nbsp;Ali Oubella ,&nbsp;Reda A. Haggam","doi":"10.1016/j.compbiolchem.2025.108692","DOIUrl":"10.1016/j.compbiolchem.2025.108692","url":null,"abstract":"<div><div>Breast cancer remains a leading cause of mortality among women, necessitating the development of non-invasive diagnostic methods. Formaldehyde (FA) has emerged as a potential biomarker for early detection of breast cancer in urine. This study explores the efficacy of boron-nitrogen-doped C60 heterofullerenes (BN_(5,6)C₅₈ and BN(6,6)C58) as highly sensitive and selective biosensors for FA detection using density functional theory (DFT). A comprehensive set of electronic, thermodynamic, and quantum chemical descriptors was employed to evaluate the sensing potential. Key computed parameters (including a significantly reduced energy gap (HLG = 0.49 eV), a high adsorption energy (Eads = −12.55 kcal/mol), a favorable Gibbs free energy change (ΔG = −12.73 kcal/mol), an enhanced dipole moment (μ = 7.425 D), increased polarizability (α = 525.640), and non-covalent interaction (NCI) analysis) collectively confirmed that BN doping significantly enhances the interaction strength with FA, with BN(6,6)C58 exhibiting the highest sensitivity (1.9 ×10¹⁷). Electronic property analyses demonstrated a reduced energy gap and enhanced charge transfer in BN(6,6)C58@FA, corroborated by molecular electrostatic potential and NCI analyses. The sensor's rapid recovery time (1.65 ×10⁻³ s) and high electrical conductivity (16 A.m⁻²) further underscore its potential for real-time breath analysis. These findings highlight BN(6,6)C58 as a promising candidate for non-invasive breast cancer diagnostics, paving the way for developing advanced electrochemical biosensors.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108692"},"PeriodicalIF":3.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling cancer stem cell marker networks: A hypergraph approach","authors":"David H. Margarit ,&nbsp;Gustavo Paccosi ,&nbsp;Marcela V. Reale ,&nbsp;Lilia M. Romanelli","doi":"10.1016/j.compbiolchem.2025.108684","DOIUrl":"10.1016/j.compbiolchem.2025.108684","url":null,"abstract":"<div><div>We propose a novel computational framework leveraging hypergraph theory to analyse cancer stem cell markers (CSCMs) across multiple organs. Hypergraphs provide a robust representation of CSCM co-expression patterns, capturing their complex multi-organ relationships more comprehensively than traditional graph-based methods. By integrating mutual information analysis and Markov models, we identify key markers driving tumour heterogeneity and metastasis, offering detailed insights into their interdependencies. This approach establishes hypergraphs as a computationally powerful tool to model cancer progression and metastatic dynamics, contributing to the understanding of complex biological systems and supporting the development of targeted therapeutic strategies.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108684"},"PeriodicalIF":3.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a breast cancer survival prediction model based on perioperative anesthesia-related drug target genes and analysis of immune microenvironment and drug sensitivity","authors":"Dongmei Yu ,&nbsp;Jiajia Li ,&nbsp;Wenjing Ma ,&nbsp;Yue Pei ,&nbsp;Yingchao Qi ,&nbsp;Tong Yu ,&nbsp;Wenkai Li ,&nbsp;Xiaohan Sun ,&nbsp;Jingyan Zhang ,&nbsp;Xuantonghe Li ,&nbsp;Longyan Liang ,&nbsp;Yunen Liu ,&nbsp;Yichen Wang","doi":"10.1016/j.compbiolchem.2025.108681","DOIUrl":"10.1016/j.compbiolchem.2025.108681","url":null,"abstract":"<div><h3>Introduction</h3><div>This study aimed to create a survival prediction model for breast cancer(BC) using perioperative anesthesia - related drug target genes(PARDTGs). It explored their immune microenvironment and drug sensitivity for personalized therapy.</div></div><div><h3>Methods</h3><div>Transcriptomic sequencing data of BC were downloaded from The Cancer Genome Atlas (TCGA) database. Common PARDTGs were retrieved from the DrugBank and ChemBL databases. Transcriptomic data were analyzed to identify differentially expressed PARDTGs (DE-PARDTGs) using rigorous statistical thresholds. A total of 101 machine learning algorithms were applied to construct PARDTG-based survival prediction models. Patients were stratified into high- and low-risk groups based on model-derived risk scores. Model performance was validated using an independent dataset from the Gene Expression Omnibus (GEO). Clinical-pathological correlations, immune profiling, and mutational landscapes were compared between risk groups in the TCGA-BRCA cohort. Drug sensitivity to commonly used therapies was predicted via transcriptomic correlations.</div></div><div><h3>Results</h3><div>We identified five DE - PARDTGs (PTGS2, TACR1, ADRB1, ABCB1, ACKR3) for a BC prognostic model. Receiver Operating Characteristic - Area Under the Curves（ROC - AUCs) for 1 -, 3 -, 5 - year overall survival(OS) were 0.722, 0.730, 0.691. TACR1 and ADRB1 high - expression meant better prognosis. Risk groups differed in immunity, with TACR1 correlating with immune checkpoints and drug sensitivity. Conclusions: The PARDTG - based model predicts BC survival independently. TACR1, key to immune response and drug sensitivity, could be a new therapeutic target. These results stress the importance of focusing on perioperative anesthesia - related drug targets in BC research.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108681"},"PeriodicalIF":3.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Alzheimer’s therapeutics via in silico strategies: Tideglusib based multi-target analogues","authors":"Samanta Gambhir,&nbsp;Manjinder Singh","doi":"10.1016/j.compbiolchem.2025.108685","DOIUrl":"10.1016/j.compbiolchem.2025.108685","url":null,"abstract":"<div><div>Alzheimer’s disease is an advanced neurodegenerative illness that disturbs cognitive behavior. Multiple factors are responsible for the etiology of Alzheimer’s disease and one of the cores neuropathologic finding is generation of hyper-phosphorylated tau. GSK-3β or Glycogen synthase kinase-3β a kinase leads to the hyperphosphorylation of tau protein at multiple sites and aggregates into neurofibrillary tangles in AD patient’s brain. Tideglusib is a drug which is under second phase of clinical trial (NCT01350362), impedes the GSK-3β at therapeutically concentration that has been established through various <em>in silico</em> techniques like scaffold morphing, pharmacokinetic, molecular docking and dynamic simulations studies. The Tideglusib based analogues showed good interactions with the catalytic dyed residue (Cys199) of GSK-3β GSK-3β, the main amino acid responsible for its tau hyperphosphorylation activity. Also, the designed analogues of Tideglusib are analyzed for its Multi targeting potential with three main receptors (GSK-3β, AChE, BACE) through molecular docking and molecular dynamic simulation approaches. SG-09 stands out with the best binding affinity and the stable ligand-protein interaction analogues in the time interval of 100 ns can be used as Multitargeting drug with further <em>in silico, in vitro and in vivo</em> clinical evaluation. This design strategy could thus reap considerable clinical and economic rewards.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108685"},"PeriodicalIF":3.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145099400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the anticancer role of alpha-phellandrene via TRPM4 channel modulation in lung cancer","authors":"Akanksha Singh ,&nbsp;Shristi Modanwal ,&nbsp;Abha Meena ,&nbsp;Nidhi Mishra","doi":"10.1016/j.compbiolchem.2025.108688","DOIUrl":"10.1016/j.compbiolchem.2025.108688","url":null,"abstract":"<div><div>Lung cancer remains one of the leading causes of death worldwide, and in major cases accounts for non-small cell lung cancer (NSCLC). Recent advances in targeted therapy have greatly improved treatment outcomes by concentrating on specific genes, proteins, and signaling pathways in tumors, providing a precise treatment method that causes less damage to healthy cells. In the context of targeted therapy, one more target biomarker has been identified, ion channels, which have been considered diverse regulators in the progression of lung cancer. Transient receptor potential (TRP) channels have captivated tremendous appreciation as promising drug targets over the past few years. Importantly, TRPM, a family of TRP that are key regulators of calcium homeostasis, have emerged as promising therapeutic targets due to their overexpression in various cancers, including lung cancer, as well as their involvement in tumor progression, metastasis, and apoptosis resistance. This study investigates the potential of naturally occurring monoterpenes as TRPM channel modulators using an <em>in silico</em> approach. Fifteen monoterpenes were selected and evaluated for their pharmacokinetic properties (ADMET), drug-likeness, and molecular docking study against TRPM2, TRPM4, TRPM5, TRPM7, and TRPM8 isoforms. Alpha-Phellandrene showed significant binding affinity toward TRPM4 (-6.0 kcal/mol) and notably shared key binding residues (ARG960, TYR964, GLU978, GLN976, PRO975, GLN973, LEU968) with the standard inhibitor 9-Phenanthrol, indicating its potential as a natural mimic. Molecular dynamics (MD) simulations further validated the structural stability of the TRPM4–alpha–phellandrene complex over 100 ns. Research findings suggested alpha-phellandrene as a promising candidate for developing TRPM4-targeted therapies in lung cancer.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108688"},"PeriodicalIF":3.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morpholine-modified thiosemicarbazones and thiazolidin-4-ones against Alzheimer’s key enzymes: From synthesis to inhibition","authors":"Yeliz Demir ,&nbsp;Halil Şenol ,&nbsp;Orhan Uluçay ,&nbsp;Şeyma Ateşoğlu S. ,&nbsp;Feyzi Sinan Tokalı","doi":"10.1016/j.compbiolchem.2025.108683","DOIUrl":"10.1016/j.compbiolchem.2025.108683","url":null,"abstract":"<div><div>Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a key therapeutic approach in the management of Alzheimer’s disease and other neurodegenerative disorders. A novel series of phenolic Mannich base-derived thiosemicarbazones and their cyclized thiazolidin-4-one analogs incorporating morpholine moieties were synthesized and characterized. Enzyme inhibition kinetics were evaluated against AChE and BChE, with cytotoxicity assessed on the BEAS-2B cell line. The most potent inhibitors were further examined via molecular docking, MM-GBSA binding free energy decomposition, and 250 ns molecular dynamics (MD) simulations to elucidate their binding mechanisms and stability. Compounds <strong>12</strong> (AChE, <em>K</em>_i = 32.83 ± 4.45 nM) and <strong>6</strong> (BChE, <em>K</em>_i = 30.13 ± 5.78 nM) exhibited the highest inhibitory activities without notable cytotoxicity at their effective concentrations. Kinetic analyses revealed competitive inhibition. Computational studies demonstrated that morpholine tertiary amine groups played a pivotal role in anchoring the ligands via persistent cation–π and hydrogen-bond interactions with key active site residues. <em>In silico</em> ADME analysis indicated that most of the synthesized compounds possess favorable pharmacokinetic properties. This combined <em>in vitro</em> and <em>in silico</em> study identifies compounds <strong>6</strong> and <strong>12</strong> as promising lead structures for cholinesterase inhibition, highlighting the critical contribution of tertiary amine moieties to binding affinity and selectivity.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108683"},"PeriodicalIF":3.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and computational evaluation of ester prodrugs of isoguvacine as potential antiseizure medications","authors":"Yan Hong Ng ,&nbsp;Muhamad Imam Muhajir ,&nbsp;Khairul Azreena Bakar ,&nbsp;Rani Maharani ,&nbsp;Unang Supratman ,&nbsp;Jalifah Latip ,&nbsp;Murni Nazira Sarian ,&nbsp;Su Datt Lam ,&nbsp;Shevin Rizal Feroz","doi":"10.1016/j.compbiolchem.2025.108678","DOIUrl":"10.1016/j.compbiolchem.2025.108678","url":null,"abstract":"<div><div>Epilepsy, a neurological disorder affecting millions worldwide, has driven the development of various antiseizure medications (ASMs). Isoguvacine (IGV), a potent and selective agonist of the GABA_A receptor (GABA_AR), has shown potential in the treatment of epilepsy and other neurological disorders. However, its low blood-brain barrier permeability impairs its ability to act effectively within the central nervous system. To address this limitation, two novel ester derivatives of IGV, <strong>E7</strong> and <strong>E14</strong>, were synthesized via Steglich esterification and evaluated through an integrated computational framework comprising density functional theory (DFT) calculations, molecular docking, molecular dynamics (MD) simulations, and <em>in silico</em> ADMET predictions. DFT analysis revealed that esterification significantly modified the electronic properties of IGV, with <strong>E14</strong> exhibiting the highest polarizability (225.895 ų) and smallest energy gap (–0.155 eV), indicative of enhanced reactivity. Molecular docking demonstrated that GABA (–8.46 kcal/mol) and IGV (–8.35 kcal/mol) exhibit similar binding affinity and complex stability with GABA_AR, supporting the reliability of our computational approach. MD simulations further confirmed the stability of these complexes, where lower RMSD, RMSF, and Rg values indicated that binding of GABA and IGV did not induce significant conformational changes in the overall receptor structure. Moreover, the derivatives were projected to exhibit optimal intestinal absorption (&gt;90%), oral bioavailability, as well as favorable safety profiles with minimal interaction risks and non-carcinogenic properties. Collectively, these <em>in silico</em> findings highlight the potential of ester prodrug design to overcome the central pharmacokinetic limitations of IGV, with <strong>E14</strong> emerging as the most promising ASM candidate for further experimental development in epilepsy therapy. Beyond identifying therapeutic advantages of <strong>E14</strong>, this study also underscores the broader value of integrated computational approaches as powerful and predictive tools in early-stage drug discovery for neurological disorders.</div></div>","PeriodicalId":10616,"journal":{"name":"Computational Biology and Chemistry","volume":"120 ","pages":"Article 108678"},"PeriodicalIF":3.1,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}