Journal of Computer-Aided Molecular Design最新文献_第10页

Insight on the mechanism of hexameric Pseudin-4 against bacterial membrane-mimetic environment 六聚假蛋白-4抗细菌膜模拟环境的机制研究

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-27 DOI: 10.1007/s10822-023-00516-2

A. S. Vinutha, R. Rajasekaran

{"title":"Insight on the mechanism of hexameric Pseudin-4 against bacterial membrane-mimetic environment","authors":"A. S. Vinutha, R. Rajasekaran","doi":"10.1007/s10822-023-00516-2","DOIUrl":"10.1007/s10822-023-00516-2","url":null,"abstract":"<div><p>As an alternative to antibiotics, Antimicrobial Peptides (AMPs) possess unique properties including cationic, amphipathic and their abundance in nature, but the exact characteristics of AMPs against bacterial membranes are still undetermined. To estimate the structural stability and functional activity of AMPs, the Pseudin AMPs (Pse-1, Pse-2, Pse-3, and Pse-4) from Hylid frog species, <i>Pseudis paradoxa</i>, an abundantly discovered source for AMPs were examined. We studied the intra-peptide interactions and thermal denaturation stability of peptides, as well as the geometrical parameters and secondary structure profiles of their conformational trajectories. On this basis, the peptides were screened out and the highly stable peptide, Pse-4 was subjected to membrane simulation in order to observe the changes in membrane curvature formed by Pse-4 insertion. Monomeric Pse-4 was found to initiate the membrane disruption; however, a stable multimeric form of Pse-4 might be competent to counterbalance the helix-coil transition and to resist the hydrophobic membrane environment. Eventually, hexameric Pse-4 on membrane simulation exhibited the hydrogen bond formation with <i>E. coli</i> bacterial membrane and thereby, leading to the formation of membrane spanning pore that allowed the entry of excess water molecules into the membrane shell, thus causing membrane deformation. Our report points out the mechanism of Pse-4 peptide against the bacterial membrane for the first time. Relatively, Pse-4 works on the barrel stave model against <i>E. coli</i> bacterial membrane; hence it might act as a good therapeutic scaffold in the treatment of multi-drug resistant bacterial strains.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 9","pages":"419 - 434"},"PeriodicalIF":3.5,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5482626","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}

引用次数: 0

Faster and more diverse de novo molecular optimization with double-loop reinforcement learning using augmented SMILES 使用增强smile的双环强化学习，更快，更多样化的从头分子优化

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-17 DOI: 10.1007/s10822-023-00512-6

Esben Jannik Bjerrum, Christian Margreitter, Thomas Blaschke, Simona Kolarova, Raquel López-Ríos de Castro

{"title":"Faster and more diverse de novo molecular optimization with double-loop reinforcement learning using augmented SMILES","authors":"Esben Jannik Bjerrum, Christian Margreitter, Thomas Blaschke, Simona Kolarova, Raquel López-Ríos de Castro","doi":"10.1007/s10822-023-00512-6","DOIUrl":"10.1007/s10822-023-00512-6","url":null,"abstract":"<div><p>Using generative deep learning models and reinforcement learning together can effectively generate new molecules with desired properties. By employing a multi-objective scoring function, thousands of high-scoring molecules can be generated, making this approach useful for drug discovery and material science. However, the application of these methods can be hindered by computationally expensive or time-consuming scoring procedures, particularly when a large number of function calls are required as feedback in the reinforcement learning optimization. Here, we propose the use of double-loop reinforcement learning with simplified molecular line entry system (SMILES) augmentation to improve the efficiency and speed of the optimization. By adding an inner loop that augments the generated SMILES strings to non-canonical SMILES for use in additional reinforcement learning rounds, we can both reuse the scoring calculations on the molecular level, thereby speeding up the learning process, as well as offer additional protection against mode collapse. We find that employing between 5 and 10 augmentation repetitions is optimal for the scoring functions tested and is further associated with an increased diversity in the generated compounds, improved reproducibility of the sampling runs and the generation of molecules of higher similarity to known ligands.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 8","pages":"373 - 394"},"PeriodicalIF":3.5,"publicationDate":"2023-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00512-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4690096","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}

引用次数: 4

On the construction of LIECE models for the serotonin receptor 5-HT(_{text {2A}})R 5-羟色胺受体5-HT LIECE模型的构建(_{text {2A}}) R

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-14 DOI: 10.1007/s10822-023-00507-3

Aida Shahraki, Jana Selent, Peter Kolb

引用次数: 0

Integrated data-driven and experimental approaches to accelerate lead optimization targeting SARS-CoV-2 main protease 整合数据驱动和实验方法，加速针对SARS-CoV-2主要蛋白酶的导联优化

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-14 DOI: 10.1007/s10822-023-00509-1

Rohith Anand Varikoti, Katherine J. Schultz, Chathuri J. Kombala, Agustin Kruel, Kristoffer R. Brandvold, Mowei Zhou, Neeraj Kumar

{"title":"Integrated data-driven and experimental approaches to accelerate lead optimization targeting SARS-CoV-2 main protease","authors":"Rohith Anand Varikoti, Katherine J. Schultz, Chathuri J. Kombala, Agustin Kruel, Kristoffer R. Brandvold, Mowei Zhou, Neeraj Kumar","doi":"10.1007/s10822-023-00509-1","DOIUrl":"10.1007/s10822-023-00509-1","url":null,"abstract":"<div><p>Identification of potential therapeutic candidates can be expedited by integrating computational modeling with domain aware machine learning (ML) models followed by experimental validation in an iterative manner. Generative deep learning models can generate thousands of new candidates, however, their physiochemical and biochemical properties are typically not fully optimized. Using our recently developed deep learning models and a scaffold as a starting point, we generated tens of thousands of compounds for SARS-CoV-2 M<sup>pro</sup> that preserve the core scaffold. We utilized and implemented several computational tools such as structural alert and toxicity analysis, high throughput virtual screening, ML-based 3D quantitative structure-activity relationships, multi-parameter optimization, and graph neural networks on generated candidates to predict biological activity and binding affinity in advance. As a result of these combined computational endeavors, eight promising candidates were singled out and put through experimental testing using Native Mass Spectrometry and FRET-based functional assays. Two of the tested compounds with quinazoline-2-thiol and acetylpiperidine core moieties showed IC<span>(_{50})</span> values in the low micromolar range: <span>(2.95pm 0.0017)</span> <span>(upmu)</span>M and 3.41±0.0015 <span>(upmu)</span>M, respectively. Molecular dynamics simulations further highlight that binding of these compounds results in allosteric modulations within the chain B and the interface domains of the M<sup>pro</sup>. Our integrated approach provides a platform for data driven lead optimization with rapid characterization and experimental validation in a closed loop that could be applied to other potential protein targets.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 8","pages":"339 - 355"},"PeriodicalIF":3.5,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4576444","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}

引用次数: 0

OFraMP: a fragment-based tool to facilitate the parametrization of large molecules OFraMP:一个基于片段的工具，便于大分子的参数化

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-13 DOI: 10.1007/s10822-023-00511-7

Martin Stroet, Bertrand Caron, Martin S. Engler, Jimi van der Woning, Aude Kauffmann, Marc van Dijk, Mohammed El-Kebir, Koen M. Visscher, Josef Holownia, Callum Macfarlane, Brian J. Bennion, Svetlana Gelpi-Dominguez, Felice C. Lightstone, Tijs van der Storm, Daan P. Geerke, Alan E. Mark, Gunnar W. Klau

{"title":"OFraMP: a fragment-based tool to facilitate the parametrization of large molecules","authors":"Martin Stroet, Bertrand Caron, Martin S. Engler, Jimi van der Woning, Aude Kauffmann, Marc van Dijk, Mohammed El-Kebir, Koen M. Visscher, Josef Holownia, Callum Macfarlane, Brian J. Bennion, Svetlana Gelpi-Dominguez, Felice C. Lightstone, Tijs van der Storm, Daan P. Geerke, Alan E. Mark, Gunnar W. Klau","doi":"10.1007/s10822-023-00511-7","DOIUrl":"10.1007/s10822-023-00511-7","url":null,"abstract":"<div><p>An Online tool for Fragment-based Molecule Parametrization (OFraMP) is described. OFraMP is a web application for assigning atomic interaction parameters to large molecules by matching sub-fragments within the target molecule to equivalent sub-fragments within the Automated Topology Builder (ATB, atb.uq.edu.au) database. OFraMP identifies and compares alternative molecular fragments from the ATB database, which contains over 890,000 pre-parameterized molecules, using a novel hierarchical matching procedure. Atoms are considered within the context of an extended local environment (buffer region) with the degree of similarity between an atom in the target molecule and that in the proposed match controlled by varying the size of the buffer region. Adjacent matching atoms are combined into progressively larger matched sub-structures. The user then selects the most appropriate match. OFraMP also allows users to manually alter interaction parameters and automates the submission of missing substructures to the ATB in order to generate parameters for atoms in environments not represented in the existing database. The utility of OFraMP is illustrated using the anti-cancer agent paclitaxel and a dendrimer used in organic semiconductor devices.</p><h3>Graphical abstract</h3><p>OFraMP applied to paclitaxel (ATB ID 35922).</p><figure><div><div><div><picture><source><img></source></picture></div></div></div></figure></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 8","pages":"357 - 371"},"PeriodicalIF":3.5,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00511-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4541924","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}

引用次数: 0

Molecular dynamics simulations reveal the inhibition mechanism of Cdc42 by RhoGDI1 分子动力学模拟揭示了RhoGDI1对Cdc42的抑制机制

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-07 DOI: 10.1007/s10822-023-00508-2

Yijing Zhang, Shiyao Chen, Taeyoung Choi, Yuzheng Qi, Qianhui Wang, Guanyi Li, Yaxue Zhao

{"title":"Molecular dynamics simulations reveal the inhibition mechanism of Cdc42 by RhoGDI1","authors":"Yijing Zhang, Shiyao Chen, Taeyoung Choi, Yuzheng Qi, Qianhui Wang, Guanyi Li, Yaxue Zhao","doi":"10.1007/s10822-023-00508-2","DOIUrl":"10.1007/s10822-023-00508-2","url":null,"abstract":"<div><p>Cell division control protein 42 homolog (Cdc42), which controls a variety of cellular functions including rearrangements of the cell cytoskeleton, cell differentiation and proliferation, is a potential cancer therapeutic target. As an endogenous negative regulator of Cdc42, the Rho GDP dissociation inhibitor 1 (RhoGDI1) can prevent the GDP/GTP exchange of Cdc42 to maintain Cdc42 into an inactive state. To investigate the inhibition mechanism of Cdc42 through RhoGDI1 at the atomic level, we performed molecular dynamics (MD) simulations. Without RhoGDI1, Cdc42 has more flexible conformations, especially in switch regions which are vital for binding GDP/GTP and regulators. In the presence of RhoGDI1, it not only can change the intramolecular interactions of Cdc42 but also can maintain the switch regions into a closed conformation through extensive interactions with Cdc42. These results which are consistent with findings of biochemical and mutational studies provide deep structural insights into the inhibition mechanisms of Cdc42 by RhoGDI1. These findings are beneficial for the development of novel therapies targeting Cdc42-related cancers.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 7","pages":"301 - 312"},"PeriodicalIF":3.5,"publicationDate":"2023-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4305400","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}

引用次数: 0

Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis 通过结合分子动力学模拟和社区网络分析阐明点突变对FGFR3抑制剂耐药性的潜在影响

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-06-03 DOI: 10.1007/s10822-023-00510-8

Bo Liu, Juntao Ding, Yugang Liu, Jianzhang Wu, Xiaoping Wu, Qian Chen, Wulan Li

{"title":"Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis","authors":"Bo Liu, Juntao Ding, Yugang Liu, Jianzhang Wu, Xiaoping Wu, Qian Chen, Wulan Li","doi":"10.1007/s10822-023-00510-8","DOIUrl":"10.1007/s10822-023-00510-8","url":null,"abstract":"<div><p>FGFR3 kinase mutations are associated with a variety of malignancies, but FGFR3 mutant inhibitors have rarely been studied. Furthermore, the mechanism of pan-FGFR inhibitors resistance caused by kinase domain mutations is still unclear. In this study, we try to explain the mechanism of drug resistance to FGFR3 mutation through global analysis and local analysis based on molecular dynamics simulation, binding free energy analysis, umbrella sampling and community network analysis. The results showed that FGFR3 mutations caused a decrease in the affinity between drugs and FGFR3 kinase, which was consistent with the reported experimental results. Possible mechanisms are that mutations affect drug-protein affinity by altering the environment of residues near the hinge region where the protein binds to the drug, or by affecting the A-loop and interfering with the allosteric communication networks. In conclusion, we systematically elucidated the underlying mechanism of pan-FGFR inhibitor resistance caused by FGFR3 mutation based on molecular dynamics simulation strategy, which provided theoretical guidance for the development of FGFR3 mutant kinase inhibitors.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 7","pages":"325 - 338"},"PeriodicalIF":3.5,"publicationDate":"2023-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00510-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4128652","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}

引用次数: 0

Insights into the coordination chemistry of antineoplastic doxorubicin with 3d-transition metal ions Zn2+, Cu2+, and VO2+: a study using well-calibrated thermodynamic cycles and chemical interaction quantum chemistry models 抗肿瘤药物多柔比星与 3d 过渡金属离子 Zn2+、Cu2+ 和 VO2+ 的配位化学透视：使用校准良好的热力学循环和化学相互作用量子化学模型进行的研究

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-05-28 DOI: 10.1007/s10822-023-00506-4

Julieta Reyna-Luna, Luis Soriano-Agueda, Christiaan Jardinez Vera, Marco Franco-Pérez

{"title":"Insights into the coordination chemistry of antineoplastic doxorubicin with 3d-transition metal ions Zn2+, Cu2+, and VO2+: a study using well-calibrated thermodynamic cycles and chemical interaction quantum chemistry models","authors":"Julieta Reyna-Luna, Luis Soriano-Agueda, Christiaan Jardinez Vera, Marco Franco-Pérez","doi":"10.1007/s10822-023-00506-4","DOIUrl":"10.1007/s10822-023-00506-4","url":null,"abstract":"<div><p>We present a computational strategy based on thermodynamic cycles to predict and describe the chemical equilibrium between the 3<i>d</i>-transition metal ions Zn<sup>2+</sup>, Cu<sup>2+</sup>, and VO<sup>2+</sup> and the widely used antineoplastic drug doxorubicin. Our method involves benchmarking a theoretical protocol to compute gas-phase quantities using DLPNO Coupled-Cluster calculations as reference, followed by estimating solvation contributions to the reaction Gibbs free energies using both explicit partial (micro)solvation steps for charged solutes and neutral coordination complexes, as well as a continuum solvation procedure for all solutes involved in the complexation process. We rationalized the stability of these doxorubicin-metal complexes by inspecting quantities obtained from the topology of their electron densities, particularly the bond critical points and non-covalent interaction index. Our approach allowed us to identify representative species in solution phase, infer the most likely complexation process for each case, and identify key intramolecular interactions involved in the stability of these compounds. To the best of our knowledge, this is the first study reporting thermodynamic constants for the complexation of doxorubicin with transition metal ions. Unlike other methods, our procedure is computationally affordable for medium-sized systems and provides valuable insights even with limited experimental data. Furthermore, it can be extended to describe the complexation process between 3<i>d-</i>transition metal ions and other bioactive ligands.\u0000</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 7","pages":"279 - 299"},"PeriodicalIF":3.5,"publicationDate":"2023-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5091618","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}

引用次数: 0

Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations 利用MD模拟和炼金术相对结合自由能计算研究SQ109类似物与分枝杆菌MmpL3转运体的结合

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-05-02 DOI: 10.1007/s10822-023-00504-6

Marianna Stampolaki, Ioannis Stylianakis, Helen I. Zgurskaya, Antonios Kolocouris

{"title":"Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations","authors":"Marianna Stampolaki, Ioannis Stylianakis, Helen I. Zgurskaya, Antonios Kolocouris","doi":"10.1007/s10822-023-00504-6","DOIUrl":"10.1007/s10822-023-00504-6","url":null,"abstract":"<div><p><i>N</i>-geranyl-<i>N</i>΄-(2-adamantyl)ethane-1,2-diamine (SQ109) is a tuberculosis drug that has high potency against <i>Mycobacterium tuberculosis (Mtb)</i> and may function by blocking cell wall biosynthesis. After the crystal structure of MmpL3 from <i>Mycobacterium smegmatis</i> in complex with SQ109 became available, it was suggested that SQ109 inhibits Mmpl3 mycolic acid transporter. Here, we showed using molecular dynamics (MD) simulations that the binding profile of nine SQ109 analogs with inhibitory potency against Mtb and alkyl or aryl adducts at C-2 or C-1 adamantyl carbon to MmpL3 was consistent with the X-ray structure of MmpL3 – SQ109 complex. We showed that rotation of SQ109 around carbon–carbon bond in the monoprotonated ethylenediamine unit favors two <i>gauche</i> conformations as minima in water and lipophilic solvent using DFT calculations as well as inside the transporter’s binding area using MD simulations. The binding assays in micelles suggested that the binding affinity of the SQ109 analogs was increased for the larger, more hydrophobic adducts, which was consistent with our results from MD simulations of the SQ109 analogues suggesting that sizeable C-2 adamantyl adducts of SQ109 can fill a lipophilic region between Y257, Y646, F260 and F649 in MmpL3. This was confirmed quantitatively by our calculations of the relative binding free energies using the thermodynamic integration coupled with MD simulations method with a mean assigned error of 0.74 kcal mol<sup>−1</sup> compared to the experimental values.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 5-6","pages":"245 - 264"},"PeriodicalIF":3.5,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00504-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4097786","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}

引用次数: 1

TargIDe: a machine-learning workflow for target identification of molecules with antibiofilm activity against Pseudomonas aeruginosa TargIDe:一种机器学习工作流程，用于对铜绿假单胞菌具有抗生素膜活性的分子进行目标识别

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-04-22 DOI: 10.1007/s10822-023-00505-5

João Carneiro, Rita P. Magalhães, Victor M. de la Oliva Roque, Manuel Simões, Diogo Pratas, Sérgio F. Sousa

{"title":"TargIDe: a machine-learning workflow for target identification of molecules with antibiofilm activity against Pseudomonas aeruginosa","authors":"João Carneiro, Rita P. Magalhães, Victor M. de la Oliva Roque, Manuel Simões, Diogo Pratas, Sérgio F. Sousa","doi":"10.1007/s10822-023-00505-5","DOIUrl":"10.1007/s10822-023-00505-5","url":null,"abstract":"<div><p>Bacterial biofilms are a source of infectious human diseases and are heavily linked to antibiotic resistance. <i>Pseudomonas aeruginosa</i> is a multidrug-resistant bacterium widely present and implicated in several hospital-acquired infections. Over the last years, the development of new drugs able to inhibit <i>Pseudomonas aeruginosa</i> by interfering with its ability to form biofilms has become a promising strategy in drug discovery. Identifying molecules able to interfere with biofilm formation is difficult, but further developing these molecules by rationally improving their activity is particularly challenging, as it requires knowledge of the specific protein target that is inhibited. This work describes the development of a machine learning multitechnique consensus workflow to predict the protein targets of molecules with confirmed inhibitory activity against biofilm formation by <i>Pseudomonas aeruginosa</i>. It uses a specialized database containing all the known targets implicated in biofilm formation by <i>Pseudomonas aeruginosa.</i> The experimentally confirmed inhibitors available on ChEMBL, together with chemical descriptors, were used as the input features for a combination of nine different classification models, yielding a consensus method to predict the most likely target of a ligand. The implemented algorithm is freely available at https://github.com/BioSIM-Research-Group/TargIDe under licence GNU General Public Licence (GPL) version 3 and can easily be improved as more data become available.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 5-6","pages":"265 - 278"},"PeriodicalIF":3.5,"publicationDate":"2023-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00505-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4845270","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}

引用次数: 0