Journal of Computer-Aided Molecular Design最新文献

{"title":"OPTUNA optimization for predicting chemical respiratory toxicity using ML models","authors":"Eman Shehab,&nbsp;Hamada Nayel,&nbsp;Mohamed Taha","doi":"10.1007/s10822-025-00597-1","DOIUrl":"10.1007/s10822-025-00597-1","url":null,"abstract":"<div><p>Predicting molecular toxicity is an important stage in the process of drug discovery. It is directly related to medical destiny and human health. This paper presents an enhanced model for chemical respiratory toxicity prediction. It used a combination of molecular descriptors and term frequency – inverse document frequency (TF-IDF) based models with different machine learning algorithms. To address class imbalance, SMOTE is applied. Appropriate hyper-parameter tuning is required to generate a better system with a classifier. So, we adjusted the hyper-parameters of various models and used the adjusted parameters to train the model. We tuned hyper-parameters using OPTUNA. Internal and external validation were used to confirm the models’ performance. According to the results, the model’s internal validation accuracy and AUC using the random forest approach were 88.6% and 93.2%. For external validation, the model’s accuracy value using random forest and Gradient Boosting Classifier were 92.2% with AUC 97%. Comparing these results with previous studies shows that our model performs better compared to them.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticancer potential of novel benzothiazolyl piperidine-3-carboxamide derivatives as CDKs and VEGFR2 multi-target kinase inhibitors","authors":"Obaid Afzal,&nbsp;Ali Altharawi,&nbsp;Safar M. Alqahtani,&nbsp;Manal A. Alossaimi,&nbsp;Taibah Aldakhil,&nbsp;Abdulmalik S. A. Altamimi,&nbsp;Alhumaidi Alabbas,&nbsp;Mubarak A. Alamri","doi":"10.1007/s10822-025-00599-z","DOIUrl":"10.1007/s10822-025-00599-z","url":null,"abstract":"<div><p>The inhibition of cyclin-dependent kinases is a viable anticancer therapy due to their critical function in regulating cell cycle progression and transcription. The present study intended to design novel benzothiazolyl piperidine-3-carboxamide derivatives as multi-target CDKs and VEGFR2 inhibitor. Novel benzothiazolyl piperidine-3-carboxamide derivatives varying smaller and bulkier <i>N</i>-substitution at piperidine motif (<b>4a–f</b>) were designed based on the key structural features of SNS-032 (a CDK and VEGFR2 inhibitor). The compounds were subjected to extra-precision docking on seven CDKs and VEGFR2 kinase targets. The results revealed superior score/interaction of compounds with three CDKs (CDK2, CDK5, and CDK6) and VEGFR2, as compared to SNS-032. The best poses of <b>3</b>, <b>4b</b>, <b>4c</b> and SNS-032 were used in WaterMap study to analyze the hydration sites. MD simulations (100 ns) in the TIP3P water model for <b>4c</b> and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC–MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds <b>3</b> (IC₅₀ 0.026 µM) and <b>4c</b> (IC₅₀ 0.048 µM) as compared to SNS-032 (IC₅₀ 0.052 µM) against CDK2, compounds <b>3</b> (IC₅₀ 0.315 µM), <b>4a</b> (IC₅₀ 0.248 µM), <b>4b</b> (IC₅₀ 0.276 µM), and <b>4c</b> (IC₅₀ 0.338 µM) as compared to SNS-032 (IC₅₀ 0.476 µM) against CDK5, compounds <b>3</b> (IC₅₀ 0.221 µM), <b>4a</b> (IC₅₀ 0.256 µM), <b>4b</b> (IC₅₀ 0.282 µM), <b>4c</b> (IC₅₀ 0.236 µM), and <b>4e</b> (IC₅₀ 0.274 µM) as compared to SNS-032 (IC₅₀ 0.365 µM) against CDK6, and comparable potency of compound <b>4b</b> (IC₅₀ 0.136 µM) with Sorafenib (IC₅₀ 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (<b>3</b> and <b>4a–f</b>) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based discovery of novel non-covalent small molecule inhibitors of USP30","authors":"Padmanabhan Anbazhagan,&nbsp;Jothi Anantharajan,&nbsp;Justina Fulwood,&nbsp;Choon Heng Low,&nbsp;Nithya Baburajendran,&nbsp;Klement Foo,&nbsp;Weijun Xu","doi":"10.1007/s10822-025-00596-2","DOIUrl":"10.1007/s10822-025-00596-2","url":null,"abstract":"<div><p>Ubiquitin-specific proteases (USPs) are crucial regulators of protein degradation pathways, influencing diverse cellular processes and disease mechanisms. Among them, USP30 plays a pivotal role in mitochondrial quality control and has been implicated in idiopathic pulmonary fibrosis (IPF), a chronic lung disease for which current therapies merely slow disease progression. The high flexibility of USP30’s catalytic site, coupled with its dependence on covalent interaction with the catalytic cysteine presents significant challenges in discovering suitable small molecule inhibitors. In this study, we identified three non-covalent small molecule inhibitors for USP30 using molecular modeling, X-ray crystallography, and virtual screening. These findings offer valuable insights and novel chemical starting points for further medicinal chemistry optimization.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational molecular design of novel class-III peptidic antagonists to competitively disrupt human PPARδ self-binding peptide","authors":"Yue Peng,&nbsp;Zilong Li,&nbsp;Yunyi Zhang,&nbsp;Haiyang Ye,&nbsp;Li Mei,&nbsp;Shuyong Shang,&nbsp;Peng Zhou","doi":"10.1007/s10822-025-00594-4","DOIUrl":"10.1007/s10822-025-00594-4","url":null,"abstract":"<div><p>Human peroxisome proliferator-activated receptor-δ (PPARδ) belongs to the nuclear receptor PPAR family that plays central roles in the regulation of glucose and lipid homeostasis and has also been implicated in cell proliferation, differentiation and inflammation. The PPARδ has a ligand-dependent transactivation function module located in the C-terminal helix 12 (H12) of its ligand-binding domain (LBD), which regulates the protein activation and inactivation by dynamically binding to and unbound from the H12-binding site (HBS) of PPARδ LBD domain, thus rendering the H12 as a so-called self-binding peptide (SBP). Currently, the existing PPARδ antagonists can be divided into two classes I and II in terms of their regulatory mechanism; the class-I antagonists competitively block natural agonists, while the class-II antagonists lock H12 out of the HBS site. In this study, class-III PPARδ antagonists were described, which directly target the HBS site and competitively disrupt the activation conformation of H12 in bound form. A self-inhibitory peptide termed HY12 with significant intrinstic disorder was derived from the H12 helical region, and we employed hydrocarbon stapling to constrain the HY12 peptide into a native-like, partially ordered helical conformation. It is confirmed that the stapling can effectively improve the peptide competition potency with native SBP for HBS site. The stapled peptides were considered as promising lead entities and can be used as the start to further develop the class-III peptidic antagonists of PPARδ.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-146/TNF-α/IL-6/osteocalcin crosstalk in anti-rheumatic potential of Galleria mellonella hemolymph from computational molecular modeling to in-vivo validation","authors":"Sara M. Ahmed,&nbsp;Elham Ali,&nbsp;Amina R. Ali,&nbsp;Mona A. Mohamed,&nbsp;Hemmat Mansour Abdelhafez,&nbsp;Alya Mashaal","doi":"10.1007/s10822-025-00595-3","DOIUrl":"10.1007/s10822-025-00595-3","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is an inflammatory autoimmune illness that persistently and recurrently affects joints. In RA, miR-146a functions as a key regulator, modulating inflammation by targeting and downregulating cytokines that promote inflammation, such as TNF-α and IL-6, whereas osteocalcin, a bone metabolism marker, plays a role in bone remodeling and joint health. The interplay between these molecules significantly influences RA progression and severity by balancing inflammation and bone integrity. Conventional antirheumatic drugs often cause varying levels of side effects. As sustainable development initiatives grow, insects are gaining interest as sustainable food sources and potential medicinal agents. Notably, the increasing <i>Galleria mellonella</i> (<i>G. mellonella</i>) population has raised concerns about the spread of honeybee viruses, affects bee products and food security, and drives economic losses in the therapeutic market. Accordingly, hemolymph has crucial defensive and immunological effects in insects and has recently been investigated as an immunomodulatory agent in parasitic in-vitro and in-vivo rat models. This work was designed to elucidate the potential immunomodulatory impact of <i>G. mellonella</i> hemolymph on the crosstalk between miR-146a, IL-6, TNF-α, and osteocalcin in the context of RA, utilizing both computational molecular modeling and in-vivo validation. Computer-aided molecular simulation for immune and RA mediators is applied through specific cell annotation, targeted pathways, and in-silico protein‒protein and gene‒gene interactions with a gene relative-tissue expression heatmap, which is based on gas chromatographic‒mass spectrometric analysis of hemolymph. Our study is the first to adapt a preliminary test to optimize hemolymph dosing and toxicity. The rats were subsequently divided into four groups: healthy control, Freund’s adjuvant-induced arthritis (utilized as a model that mimics human RA), methotrexate-treated arthritis, and hemolymph-treated arthritis groups. Our findings indicate that hemolymph contains valuable active compounds that have anti-inflammatory and antioxidant potential, increasing the impact of recovery on diseased joints in comparison with the arthritic and methotrexate groups. This is the first report investigating the maximum inhibition rate of <i>G. mellonella</i> hemolymph as an immunomodulatory and anti-inflammatory agent in an arthritic model.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-025-00595-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the sequence-dependent unfolding pathways of an RNA pseudoknot with steered molecular dynamics","authors":"Akansha Pandit,&nbsp;Shubham Srivastava,&nbsp;Neeraj Kumar,&nbsp;Devesh M. Sawant","doi":"10.1007/s10822-025-00598-0","DOIUrl":"10.1007/s10822-025-00598-0","url":null,"abstract":"<div><p>Programmed ribosomal frameshifting in Simian retrovirus-1 (SRV-1) is sensitive to the mechanical properties of an RNA pseudoknot. Unravelling these mechanical intricacies via unfolding reveals fundamental insights into their structural dynamics. Using constant velocity steered molecular dynamics (CV-SMD) simulations, we explored the unfolding dynamics and the impact of mutations on the unfolding pathway of the pseudoknot. Except for A28C, A/U to C mutations that disrupt base triples between the loop 2 and stem 1 significantly weaken the pseudoknot and make it more susceptible to unfolding. Complementary mutations in 3 base pairs of the stem region (S1) enhanced its susceptibility to disruption except for Mut5 (S2). We quantitatively assessed the variations in unfolding pathways by analysing the opening of distinct Canonical (WC) and non-canonical (NWC) interactions, force-extension curves, and potential mean force profiles (as a guiding decision for planning mutations). These findings offer a quantified perspective, showcasing the potential of utilizing the unfolding pathways of RNA pseudoknots to explore the programmability of RNA structures. This insight proves valuable for designing RNA-PROTACS and RNA-aptamers, allowing for the assessment and manipulation of their biological folding/unfolding processes.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the anti-diabetic potential of the Vigna sesquipedalis using in vitro, in vivo and computational models","authors":"Hammad Ahmad,&nbsp;Ashraf Ullah Khan,&nbsp;Waqas Alam,&nbsp;Hany W. Darwish,&nbsp;Abdul Saboor Pirzada,&nbsp;Haroon Khan","doi":"10.1007/s10822-025-00591-7","DOIUrl":"10.1007/s10822-025-00591-7","url":null,"abstract":"<div><p><i>Vigna sesquipedalis</i> is traditionally used for the treatment of various disorders including diabetes but without scientific rational. Therefore, the current study was designed to evaluate its anti-diabetic potential. Antioxidant activity was assessed through DPPH and ABTS radical scavenging assays, while α-glucosidase and α-amylase inhibitory activities for anti-diabetic potential. Based on in vitro results, acute toxicity tests were performed, followed by in vivo studies using streptozotocin-induced diabetic model in mice. The ethyl acetate fraction exhibited the highest antioxidant potential, followed by crude extract. The methanolic crude extract showed the strongest in <i>vitro</i> antidiabetic activity. It was also found to be non-toxic up to 2000 mg/kg body weight. In vivo, the crude extract significantly (P &lt; 0.05) improved body weight and displayed significant anti-diabetic effects. Further analysis of liver glycogen, serum insulin, glycosylated hemoglobin, and histopathology supported the extract overall performance. The virtual screening results showed highest binding energy of the Cyanidin-3-0-G (Cyanidin) with the amylase, Daucosterol with the GLP1, and Psoralidin with the Glucosidase. Similarly, MD simulation of the top hits was performed to investigate the dynamic stability and results showed that the ligand–protein system remains stable for during the simulation. The thermodynamic stability of the system was assessed by performing the binding free energy calculation using MM-PBSA/GBSA. The results of the binding free energy calculations showed favorable binding energies ligand–protein system. In short, the results illustrated potential as a pharmaceutical drug for insulin-dependent diabetes mellitus.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, TD-DFT calculations, molecular docking and ADME studies of new spiro-oxindole derivatives containing 5(4H)-oxazolone as anti-viral and anti-bacterial agents","authors":"N. Madadi Mahani,&nbsp;H. Hamidian,&nbsp;S. Fozooni,&nbsp;M. Salajeghe","doi":"10.1007/s10822-025-00593-5","DOIUrl":"10.1007/s10822-025-00593-5","url":null,"abstract":"<div><p>Spiro pyrrolidine oxindole and oxazolone compounds have been widely used in medicinal chemistry. They can show anti-viral, anti-diabetic, anti-cancer, anti-bacterial, anti-stress, anti-allergic, and anti-inflammatory effects. The 1,3-dipolar cycloaddition reaction, initiated by the in situ formation of an azomethine ylide, serves as a highly effective synthetic approach for constructing pyrrolidine-appended and pyrrolidine-fused heterocycles. Herein, efficient synthesis of 5 new derivatives of spiropyrrolidine oxindole framework of azomethin ylied with 4-arylidine- 5(4H)-oxasolone as dipolarophile via the one-pot multicomponent 1, 3-dipolar cycloaddition is reported. The chemical structures of the newly synthesized analogs were determined through an analysis of their spectroscopic data. In continuation, biological activity and reactivity of derivatives of spirooxindole were evaluated using computational chemistry methods such as molecular docking, and density functional theory. Also, their pharmacokinetic properties were investigated to evaluate the risk of toxicity using SWISS ADME and PKCSM online sites. In the investigation of molecular docking, the interaction of five spirooxindole derivatives with 6W63 proteins (the main protease of COVID-19) and 4EMV (ATP topoisomerase inhibitor) was studied to investigate their anti-viral and anti-bacterial properties.Based on the analysis of docking, derivatives d and e have antiviral activity with 6w63 protein and interaction b molecule with 4emv protein shows more suitable antibacterial activity. Study of reactivity descriptors obtained from quantum mechanical calculations showed that the reactivity of all compounds is almost the same and compound c is substituted by fluorine; with the formula C₂₆H₂₀FN₃O₃ it is more than other compounds. Pharmacokinetic studies showed that all compounds have high digestive and intestinal absorption and low toxicity which is an important parameter for a drug. Molecular docking, ADMET analysis, and TD-DFT analysis are used to assess the drug-likeness of <i>c</i> compound as both antiviral and anti-bacterial agents.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Convolidine as potent BACE1 inhibitor for Alzheimer’s disease; in-silico coupled with in-vitro assessment","authors":"Anuroopa G. Nadh,&nbsp;M. Jitha Kunhikrishnan,&nbsp;Vishal Ravi,&nbsp;Krishnapriya Ramakrishnan,&nbsp;Niyas Rehman,&nbsp;Krishna S. B. Adithya,&nbsp;Amjesh Revikumar,&nbsp;P. R. Sudhakaran,&nbsp;Rajesh Raju","doi":"10.1007/s10822-025-00592-6","DOIUrl":"10.1007/s10822-025-00592-6","url":null,"abstract":"<div><p>Alzheimer’s Disease is a chronic progressive neurodegenerative disorder characterized by impaired intellect and cognitive functions. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD) by initiating the amyloid cascade. Despite significant clinical efforts, most BACE1 inhibitors have failed to yield potent pharmacological effects. Our previous study, identified a group of natural compounds with satisfying pharmacological profiles with high affinity to BACE1, out of which the compound, ‘convolidine’ emerged as the most promising candidate based on the in-silico parameters such as docking score, interacting residues, binding energy, drug-likeness, ADMET, and biological activity prediction. The present study focused on the inhibitory potential of convolidine against BACE1 using dynamics simulation followed by protein-protein docking and in-vitro validation. Molecular dynamics simulation demonstrated that the BACE1-convolidine complex remained stable throughout the entire 200 ns simulation period. Also, the results of the post-dynamic docking study showed a reduced substrate affinity of BACE1 to its substrate, APP (Amyloid precursor protein), when BACE1 is bound to convolidine, suggesting compounds inhibitory potential. This in-silico assessment was validated in-vitro using a FRET-based BACE1 activity assay, where the result well aligned with the computational predictions. The findings revealed that convolidine could effectively inhibit BACE1, with an IC50 value of 0.49 µM, providing a solid foundation for its development as a promising therapeutic agent for AD management.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4","authors":"Vera A. Spanke,&nbsp;Valentin J. Egger-Hoerschinger,&nbsp;Veronika Ruzsanyi,&nbsp;Klaus R. Liedl","doi":"10.1007/s10822-025-00589-1","DOIUrl":"10.1007/s10822-025-00589-1","url":null,"abstract":"<div><p>Cytochrome P450 3A4 (CYP3A4) is a membrane bound monooxygenase. It metabolizes the largest proportion of all orally ingested drugs. Ligands can enter and exit the enzyme through flexible tunnels, which co-determine CYP3A4’s ligand promiscuity. The flexibility can be represented by distinct conformational states of the enzyme. However, previous state definitions relied solely on crystal structures. We employed conventional molecular dynamics (cMD) simulations to sample the conformational space of CYP3A4. Five conformationally different crystal structures embedded in a membrane were simulated for 1 µs each. A Markov state model (MSM) coupled with spectral clustering (Robust Perron Cluster Analysis PCCA +) resulted in three distinct states: Two open conformations and an intermediate conformation. The tunnels inside CYP3A4 were calculated with CAVER3.0. Notably, we observed variations in bottleneck radii compared to those derived from crystallographic data. We want to point out the importance of simulations to characterize the dynamic behaviour. Moreover, we identified a mechanism, in which the membrane supports the opening of a tunnel. Therefore, CYP3A4 must be investigated in its membrane-bound state.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-025-00589-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}