Molecular Informatics最新文献_第10页

Artificial neural network models driven novel virtual screening workflow for the identification and biological evaluation of BACE1 inhibitors. 人工神经网络模型驱动新的虚拟筛选工作流程，用于BACE1抑制剂的鉴定和生物学评价。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-03-01 DOI: 10.1002/minf.202200113

Kushagra Kashyap, Lalita Panigrahi, Shakil Ahmed, Mohammad Siddiqi

{"title":"Artificial neural network models driven novel virtual screening workflow for the identification and biological evaluation of BACE1 inhibitors.","authors":"Kushagra Kashyap, Lalita Panigrahi, Shakil Ahmed, Mohammad Siddiqi","doi":"10.1002/minf.202200113","DOIUrl":"https://doi.org/10.1002/minf.202200113","url":null,"abstract":"Beta-site amyloid-β precursor protein-cleaving enzyme 1 (BACE1) is a transmembrane aspartic protease and has shown potential as a possible therapeutic target for Alzheimer's disease. This aggravating disease involves the aberrant production of β amyloid plaques by BACE1 which catalyzes the rate-limiting step by cleaving the amyloid precursor protein (APP), generating the neurotoxic amyloid β protein that aggregates to form plaques leading to neurodegeneration. Therefore, it is indispensable to inhibit BACE1, thus modulating the APP processing. In this study, we present a workflow that utilizes a multi-stage virtual screening protocol for identifying potential BACE1 inhibitors by employing multiple artificial neural network-based models. Collectively, all the hyperparameter tuned models were assigned a task to virtually screen Maybridge library, thus yielding a consensus of 41 hits. The majority of these hits exhibited optimal pharmacokinetic properties confirmed by high central nervous system multiparameter optimization (CNS-MPO) scores. Further shortlisting of 8 compounds by molecular docking into the active site of BACE1 and their subsequent in-vitro evaluation identified 4 compounds as potent BACE1 inhibitors with IC50 values falling in the range 0.028-0.052 μM and can be further optimized with medicinal chemistry efforts to improve their activity.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9284492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

GB-score: Minimally designed machine learning scoring function based on distance-weighted interatomic contact features. GB-score:基于距离加权原子间接触特征的最小设计机器学习评分功能。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-03-01 DOI: 10.1002/minf.202200135

Milad Rayka, Rohoullah Firouzi

{"title":"GB-score: Minimally designed machine learning scoring function based on distance-weighted interatomic contact features.","authors":"Milad Rayka, Rohoullah Firouzi","doi":"10.1002/minf.202200135","DOIUrl":"https://doi.org/10.1002/minf.202200135","url":null,"abstract":"In recent years, thanks to advances in computer hardware and dataset availability, data-driven approaches (like machine learning) have become one of the essential parts of the drug design framework to accelerate drug discovery procedures. Constructing a new scoring function, a function that can predict the binding score for a generated protein-ligand pose during docking procedure or a crystal complex, based on machine and deep learning has become an active research area in computer-aided drug design. GB-Score is a state-of-the-art machine learning-based scoring function that utilizes distance-weighted interatomic contact features, PDBbind-v2019 general set, and Gradient Boosting Trees algorithm to the binding affinity prediction. The distance-weighted interatomic contact featurization method used the distance between different ligand and protein atom types for numerical representation of the protein-ligand complex. GB-Score attains Pearson's correlation 0.862 and RMSE 1.190 on the CASF-2016 benchmark test in the scoring power metric. GB-Score's codes are freely available on the web at https://github.com/miladrayka/GB_Score.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9646353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Automated detection of toxicophores and prediction of mutagenicity using PMCSFG algorithm. 基于PMCSFG算法的毒物团自动检测及致突变性预测。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-03-01 DOI: 10.1002/minf.202200232

Alban Lepailleur, Leander Schietgat, Bertrand Cuissart, Kurt De Grave, Kyriakos Efthymiadis, Ronan Bureau, Bruno Crémilleux, Jan Ramon

引用次数: 0

NMSDR: Drug repurposing approach based on transcriptome data and network module similarity. NMSDR:基于转录组数据和网络模块相似性的药物再利用方法。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-03-01 DOI: 10.1002/minf.202200077

Ülkü Ünsal, Ali Cüvitoğlu, Kemal Turhan, Zerrin Işik

{"title":"NMSDR: Drug repurposing approach based on transcriptome data and network module similarity.","authors":"Ülkü Ünsal, Ali Cüvitoğlu, Kemal Turhan, Zerrin Işik","doi":"10.1002/minf.202200077","DOIUrl":"https://doi.org/10.1002/minf.202200077","url":null,"abstract":"Computational drug repurposing aims to discover new treatment regimens by analyzing approved drugs on the market. This study proposes previously approved compounds that can change the expression profile of disease-causing proteins by developing a network theory-based drug repurposing approach. The novelty of the proposed approach is an exploration of module similarity between a disease-causing network and a compound-specific interaction network; thus, such an association leads to more realistic modeling of molecular cell responses at a system biology level. The overlap of the disease network and each compound-specific network is calculated based on a shortest-path similarity of networks by accounting for all protein pairs between networks. A higher similarity score indicates a significant potential of a compound. The approach was validated for breast and lung cancers. When all compounds are sorted by their normalized-similarity scores, 36 and 16 drugs are proposed as new candidates for breast and lung cancer treatment, respectively. A literature survey on candidate compounds revealed that some of our predictions have been clinically investigated in phase II/III trials for the treatment of two cancer types. As a summary, the proposed approach has provided promising initial results by modeling biochemical cell responses in a network-level data representation.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9284483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Entropy-based lamarckian quantum-behaved particle swarm optimization for flexible ligand docking. 基于熵的柔性配体对接拉马克量子粒子群优化。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-03-01 DOI: 10.1002/minf.202200080

Qi You, Chao Li, Jun Sun, Vasile Palade, Feng Pan

{"title":"Entropy-based lamarckian quantum-behaved particle swarm optimization for flexible ligand docking.","authors":"Qi You, Chao Li, Jun Sun, Vasile Palade, Feng Pan","doi":"10.1002/minf.202200080","DOIUrl":"https://doi.org/10.1002/minf.202200080","url":null,"abstract":"AutoDock is a widely used software for flexible ligand docking problems since it is open source and easy to be implemented. In this paper, a novel hybrid algorithm is proposed and applied in the docking environment of AutoDock version 4.2.6 in order to enhance the accuracy and the efficiency for dockings with flexible ligands. This search algorithm, called entropy‐based Lamarckian quantum‐behaved particle swarm optimization (ELQPSO), is a combination of the QPSO with an entropy‐based update strategy and the Solis and Wet local search (SWLS) method. By using the PDBbind core set v.2016, the ELQPSO is compared with the Lamarckian genetic algorithm (LGA), Lamarckian particle swarm optimization (LPSO) and Lamarckian QPSO (LQPSO). The experimental results reveal that the corresponding docking program of ELQPSO, named as EQDOCK in this paper, has a competitive performance in dealing with the protein‐ligand docking problems. Moreover, for the test cases with different number of torsions, the EQDOCK outperforms the other three docking programs in finding docking conformations with small root mean squared deviation (RMSD) values in most cases. In particular, it has an advantage of solving highly flexible ligand docking problems over the others.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9646350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post-processing. 通过对接和量子化学后处理鉴定的新型因子XIIa抑制剂。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-02-01 DOI: 10.1002/minf.202200205

Ivan Ilin, Nadezhda Podoplelova, Alexey Sulimov, Danil Kutov, Anna Tashchilova, Mikhail Panteleev, Khidmet Shikhaliev, Mikhail Krysin, Nadezhda Stolpovskaya, Andrey Potapov, Vladimir Sulimov

{"title":"Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post-processing.","authors":"Ivan Ilin, Nadezhda Podoplelova, Alexey Sulimov, Danil Kutov, Anna Tashchilova, Mikhail Panteleev, Khidmet Shikhaliev, Mikhail Krysin, Nadezhda Stolpovskaya, Andrey Potapov, Vladimir Sulimov","doi":"10.1002/minf.202200205","DOIUrl":"https://doi.org/10.1002/minf.202200205","url":null,"abstract":"Antithrombotic agents based on factor XIIa inhibitors can become a new class of drugs to manage conditions associated with thrombosis. Herein, we report identification of two novel classes of factor XIIa inhibitors. The first one is triazolopyrimidine derivatives designed on the basis of the literature aminotriazole hit and identified using virtual screening of the focused library. The second class is a spirocyclic furo[3,4-c]pyrrole derivatives identified by virtual screening of a large chemical library of drug-like compounds performed in a previous study but confirmed in vitro here. In both cases, the prediction of inhibitory activity is based on the score of the SOL docking program, which uses the MMFF94 force field to calculate the binding energy. For the best ligands selected in virtual screening of the large chemical library, postprocessing with the PM7 semiempirical quantum-chemical method was used to calculate the enthalpy of protein-ligand binding to prioritize 16 compounds for testing in enzymatic assay, and one of them demonstrated micromolar activity. For triazolopyrimidine library, 21 compounds were prioritized for the testing based on docking scores, and visual inspection of docking poses. Of these, 4 compounds showed inhibition of factor XIIa at 30 μM.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10828827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

FSDscore: An Effective Target-focused Scoring Criterion for Virtual Screening. FSDscore:一种有效的以目标为中心的虚拟筛选评分标准。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-02-01 DOI: 10.1002/minf.202200039

Yi Hua, Dingfang Huang, Li Liang, Xu Qian, Xiaowen Dai, Yuan Xu, Haodi Qiu, Tao Lu, Haichun Liu, Yadong Chen, Yanmin Zhang

{"title":"FSDscore: An Effective Target-focused Scoring Criterion for Virtual Screening.","authors":"Yi Hua, Dingfang Huang, Li Liang, Xu Qian, Xiaowen Dai, Yuan Xu, Haodi Qiu, Tao Lu, Haichun Liu, Yadong Chen, Yanmin Zhang","doi":"10.1002/minf.202200039","DOIUrl":"https://doi.org/10.1002/minf.202200039","url":null,"abstract":"Improving screening efficiency is one of the most challenging tasks of virtual screening (VS). In this work, we propose an effective target-focused scoring criterion for VS and apply it to the screening of a specific target scaffold replacement library constructed by enumeration of suitable substitution fragments and R-groups of known ligands. This criterion is based on both ligand- and structure-based scoring methods, which includes feature maps, 3D shape similarity, and the pairwise distance information between proteins and ligands (FSDscore). It is precisely due to the hybrid advantages of ligand- and structure-based approaches that FSDscore performs far better on the validation dataset than other scoring methods. We apply FSDscore to the VS of different kinase targets, MERTK (Mer tyrosine kinase) and ABL1 (tyrosine-protein kinase ABL1) in order to avoid occasionality. Finally, a VS case study shows the potential and effectiveness of our scoring criterion in drug discovery and molecular dynamics simulation further verifies its powerful ability.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10776295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Speed vs Accuracy: Effect on Ligand Pose Accuracy of Varying Box Size and Exhaustiveness in AutoDock Vina. 速度与精度:不同盒子尺寸和耗竭度对配体位姿精度的影响。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-02-01 DOI: 10.1002/minf.202200188

Rupesh Agarwal, Jeremy C Smith

{"title":"Speed vs Accuracy: Effect on Ligand Pose Accuracy of Varying Box Size and Exhaustiveness in AutoDock Vina.","authors":"Rupesh Agarwal, Jeremy C Smith","doi":"10.1002/minf.202200188","DOIUrl":"https://doi.org/10.1002/minf.202200188","url":null,"abstract":"Structure-based virtual high-throughput screening involves docking chemical libraries to targets of interest. A parameter pertinent to the accuracy of the resulting pose is the root mean square deviation (RMSD) from a known crystallographic structure, i. e., the 'docking power'. Here, using a popular algorithm, Autodock Vina, as a model program, we evaluate the effects of varying two common docking parameters: the box size (the size of docking search space) and the exhaustiveness of the global search (the number of independent runs starting from random ligand conformations) on the RMSD from the PDBbind v2017 refined dataset of experimental protein-ligand complexes. Although it is clear that exhaustiveness is an important parameter, there is wide variation in the values used, with variation between 1 and >100. We, therefore, evaluated a combination of cubic boxes of different sizes and five exhaustiveness values (1, 8, 25, 50, 75, 100) within the range of those commonly adopted. The results show that the default exhaustiveness value of 8 performs well overall for most box sizes. In contrast, for all box sizes, but particularly for large boxes, an exhaustiveness value of 1 led to significantly higher median RMSD (mRMSD) values. The docking power was slightly improved with an exhaustiveness of 25, but the mRMSD changes little with values higher than 25. Therefore, although low exhaustiveness is computationally faster, the results are more likely to be far from reality, and, conversely, values >25 led to little improvement at the expense of computational resources. Overall, we recommend users to use at least the default exhaustiveness value of 8 for virtual screening calculations.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10828817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Quantum-based Modeling of Protein-ligand Interaction: The Complex of RutA with Uracil and Molecular Oxygen. 蛋白质-配体相互作用的量子建模:RutA与尿嘧啶和分子氧的配合物。

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-02-01 DOI: 10.1002/minf.202200175

Igor V Polyakov, Alexander V Nemukhin, Tatiana M Domratcheva, Anna M Kulakova, Bella L Grigorenko

{"title":"Quantum-based Modeling of Protein-ligand Interaction: The Complex of RutA with Uracil and Molecular Oxygen.","authors":"Igor V Polyakov, Alexander V Nemukhin, Tatiana M Domratcheva, Anna M Kulakova, Bella L Grigorenko","doi":"10.1002/minf.202200175","DOIUrl":"https://doi.org/10.1002/minf.202200175","url":null,"abstract":"Modern quantum-based methods are employed to model interaction of the flavin-dependent enzyme RutA with the uracil and oxygen molecules. This complex presents the structure of reactants for the chain of chemical reactions of monooxygenation in the enzyme active site, which is important in drug metabolism. In this case, application of quantum-based approaches is an essential issue, unlike conventional modeling of protein-ligand interaction with force fields using molecular mechanics and classical molecular dynamics methods. We focus on two difficult problems to characterize the structure of reactants in the RutA-FMN-O2 -uracil complex, where FMN stands for the flavin mononucleotide species. First, location of a small O2 molecule in the triplet spin state in the protein cavities is required. Second, positions of both ligands, O2 and uracil, must be specified in the active site with a comparable accuracy. We show that the methods of molecular dynamics with the interaction potentials of quantum mechanics/molecular mechanics theory (QM/MM MD) allow us to characterize this complex and, in addition, to surmise possible reaction mechanism of uracil oxygenation by RutA.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10828812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Inhibitor Assessment against the LpxC Enzyme of Antibiotic-resistant Acinetobacter baumannii Using Virtual Screening, Dynamics Simulation, and in vitro Assays. 基于虚拟筛选、动态模拟和体外实验的耐药鲍曼不动杆菌LpxC酶抑制剂评估

IF 3.6 4区医学

Molecular Informatics Pub Date : 2023-02-01 DOI: 10.1002/minf.202200061

Manel Zoghlami, Maroua Oueslati, Zarrin Basharat, Najla Sadfi-Zouaoui, Abdelmonaem Messaoudi

{"title":"Inhibitor Assessment against the LpxC Enzyme of Antibiotic-resistant Acinetobacter baumannii Using Virtual Screening, Dynamics Simulation, and in vitro Assays.","authors":"Manel Zoghlami, Maroua Oueslati, Zarrin Basharat, Najla Sadfi-Zouaoui, Abdelmonaem Messaoudi","doi":"10.1002/minf.202200061","DOIUrl":"https://doi.org/10.1002/minf.202200061","url":null,"abstract":"Background: Bacterial resistance is currently a significant global public health problem. Acinetobacter baumannii has been ranked in the list of the World Health Organization as the most critical and priority pathogen for which new antibiotics are urgently needed. In this context, computational methods play a central role in the modern drug discovery process. The purpose of the current study was to identify new potential therapeutic molecules to neutralize MDR A. baumannii bacteria.Methods: A total of 3686 proteins retrieved from the A. baumannii proteome were subjected to subtractive proteomic analysis to narrow down the spectrum of drug targets. The SWISS-MODEL server was used to perform a 3D homology model of the selected target protein. The SAVES server was used to evaluate the overall quality of the model. A dataset of 74500 analogues retrieved from the PubChem database was docked with LpxC using the AutoDock software.Results: In this study, we predicted a putative new inhibitor for the Lpxc enzyme of A. baumannii. The LpxC enzyme was selected as the most appropriate drug target for A. baumannii. According to the virtual screening results, N-[(2S)-3-amino-1-(hydroxyamino)-1-oxopropan-2-yl]-4-(4-bromophenyl) benzamide (CS250) could be a promising drug candidate targeting the LpxC enzyme. This molecule shows polar interactions with six amino acids and non-polar interactions with eight other residues. In vitro experimental validation was performed through the inhibition assay.Conclusion: To the best of our knowledge, this is the first study that suggests CS250 as a promising inhibitory molecule that can be exploited to target this gram-negative pathogen.","PeriodicalId":18853,"journal":{"name":"Molecular Informatics","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10776275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1