Journal of Computer-Aided Molecular Design最新文献_第9页

Efficient screening of protein-ligand complexes in lipid bilayers using LoCoMock score 使用LoCoMock评分有效筛选脂质双分子层中的蛋白质配体复合物

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-03-21 DOI: 10.1007/s10822-023-00502-8

Rikuri Morita, Yasuteru Shigeta, Ryuhei Harada

{"title":"Efficient screening of protein-ligand complexes in lipid bilayers using LoCoMock score","authors":"Rikuri Morita, Yasuteru Shigeta, Ryuhei Harada","doi":"10.1007/s10822-023-00502-8","DOIUrl":"10.1007/s10822-023-00502-8","url":null,"abstract":"<div><p>Membrane proteins are attractive targets for drug discovery due to their crucial roles in various biological processes. Studying the binding poses of amphipathic molecules to membrane proteins is essential for understanding the functions of membrane proteins and docking simulations can facilitate the screening of protein–ligand complexes at low computational costs. However, identifying docking poses for a ligand in non-aqueous environments such as lipid bilayers can be challenging. To address this issue, we propose a new docking score called log<i>P</i>-corrected membrane docking (LoCoMock) score. To screen putative protein–ligand complexes embedded in a membrane, the LoCoMock score considers the affinity between a target ligand and the membrane. It combines the docking score of the protein–ligand complex with the log<i>P</i> of the target ligand. In demonstrations using several model ligands, the LoCoMock score screened more putative complexes than the conventional docking score. As extended docking, the LoCoMock score makes it possible to screen membrane proteins more effectively as drug targets than the conventional docking.</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 4","pages":"217 - 225"},"PeriodicalIF":3.5,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4835615","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: 1

MM/GBSA prediction of relative binding affinities of carbonic anhydrase inhibitors: effect of atomic charges and comparison with Autodock4Zn MM/GBSA预测碳酸酐酶抑制剂的相对结合亲和力:原子电荷的影响以及与Autodock4Zn的比较

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-03-17 DOI: 10.1007/s10822-023-00499-0

Mackenzie Taylor, Junming Ho

{"title":"MM/GBSA prediction of relative binding affinities of carbonic anhydrase inhibitors: effect of atomic charges and comparison with Autodock4Zn","authors":"Mackenzie Taylor, Junming Ho","doi":"10.1007/s10822-023-00499-0","DOIUrl":"10.1007/s10822-023-00499-0","url":null,"abstract":"<div><p>Carbonic anhydrase is an attractive drug target for the treatment of many diseases. This paper examines the ability of end-state MM/GBSA methods to rank inhibitors of carbonic anhydrase in terms of their binding affinities. The MM/GBSA binding energies were evaluated using different atomic charge schemes (Mulliken, ESP and NPA) at different levels of theories, including Hartree–Fock, B3LYP-D3(BJ), and M06-2X with the 6–31G(d,p) basis set. For a large test set of 32 diverse inhibitors, the use of B3LYP-D3(BJ) ESP atomic charges yielded the strongest correlation with experiment (R<sup>2</sup> = 0.77). The use of the recently enhanced Autodock Vina and zinc optimised AD4<sub>Zn</sub> force field also predicted ligand binding affinities with moderately strong correlation (R<sup>2</sup> = 0.64) at significantly lower computational cost. However, the docked poses deviate significantly from crystal structures. Overall, this study demonstrates the applicability of docking to estimate ligand binding affinities for a diverse range of CA inhibitors, and indicates that more theoretically robust MM/GBSA simulations show promise for improving the accuracy of predicted binding affinities, as long as a validated set of parameters is used.</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 4","pages":"167 - 182"},"PeriodicalIF":3.5,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00499-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4689661","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

Structural mechanism of Fab domain dissociation as a measure of interface stability 作为界面稳定性测度的Fab畴解离的结构机理

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-03-15 DOI: 10.1007/s10822-023-00501-9

Nancy D. Pomarici, Franz Waibl, Patrick K. Quoika, Alexander Bujotzek, Guy Georges, Monica L. Fernández-Quintero, Klaus R. Liedl

{"title":"Structural mechanism of Fab domain dissociation as a measure of interface stability","authors":"Nancy D. Pomarici, Franz Waibl, Patrick K. Quoika, Alexander Bujotzek, Guy Georges, Monica L. Fernández-Quintero, Klaus R. Liedl","doi":"10.1007/s10822-023-00501-9","DOIUrl":"10.1007/s10822-023-00501-9","url":null,"abstract":"<div><p>Therapeutic antibodies should not only recognize antigens specifically, but also need to be free from developability issues, such as poor stability. Thus, the mechanistic understanding and characterization of stability are critical determinants for rational antibody design. In this study, we use molecular dynamics simulations to investigate the melting process of 16 antigen binding fragments (Fabs). We describe the Fab dissociation mechanisms, showing a separation in the V<sub>H</sub>–V<sub>L</sub> and in the C<sub>H</sub>1–C<sub>L</sub> domains. We found that the depths of the minima in the free energy curve, corresponding to the bound states, correlate with the experimentally determined melting temperatures. Additionally, we provide a detailed structural description of the dissociation mechanism and identify key interactions in the CDR loops and in the C<sub>H</sub>1–C<sub>L</sub> interface that contribute to stabilization. The dissociation of the V<sub>H</sub>–V<sub>L</sub> or C<sub>H</sub>1–C<sub>L</sub> domains can be represented by conformational changes in the bend angles between the domains. Our findings elucidate the melting process of antigen binding fragments and highlight critical residues in both the variable and constant domains, which are also strongly germline dependent. Thus, our proposed mechanisms have broad implications in the development and design of new and more stable antigen binding fragments.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 4","pages":"201 - 215"},"PeriodicalIF":3.5,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00501-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4621916","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: 2

Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study MRTX1133对KRASG12D的抑制机制:分子动力学模拟和马尔可夫状态模型研究

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-02-28 DOI: 10.1007/s10822-023-00498-1

Fanglin Liang, Zhengzhong Kang, Xianqiang Sun, Jiao Chen, Xuemin Duan, Hu He, Jianxin Cheng

{"title":"Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study","authors":"Fanglin Liang, Zhengzhong Kang, Xianqiang Sun, Jiao Chen, Xuemin Duan, Hu He, Jianxin Cheng","doi":"10.1007/s10822-023-00498-1","DOIUrl":"10.1007/s10822-023-00498-1","url":null,"abstract":"<div><p>The mutant KRAS was considered as an “undruggable” target for decades, especially KRAS<sup>G12D</sup>. It is a great challenge to develop the inhibitors for KRAS<sup>G12D</sup> which lacks the thiol group for covalently binding ligands. The discovery of MRTX1133 solved the dilemma. Interestingly, MRTX1133 can bind to both the inactive and active states of KRAS<sup>G12D</sup>. The binding mechanism of MRTX1133 with KRAS<sup>G12D</sup>, especially how MRTX1133 could bind the active state KRAS<sup>G12D</sup> without triggering the active function of KRAS<sup>G12D</sup><sub>,</sub> has not been fully understood. Here, we used a combination of all-atom molecular dynamics simulations and Markov state model (MSM) to understand the inhibition mechanism of MRTX1133 and its analogs. The stationary probabilities derived from MSM show that MRTX1133 and its analogs can stabilize the inactive or active states of KRAS<sup>G12D</sup> into different conformations. More remarkably, by scrutinizing the conformational differences, MRTX1133 and its analogs were hydrogen bonded to Gly60 to stabilize the switch II region and left switch I region in a dynamically inactive conformation, thus achieving an inhibitory effect. Our simulation and analysis provide detailed inhibition mechanism of KRAS<sup>G12D</sup> induced by MRTX1133 and its analogs. This study will provide guidance for future design of novel small molecule inhibitors of KRAS<sup>G12D</sup>.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 3","pages":"157 - 166"},"PeriodicalIF":3.5,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5079812","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: 1

GPCRLigNet: rapid screening for GPCR active ligands using machine learning GPCRLigNet:利用机器学习快速筛选GPCR活性配体

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-02-25 DOI: 10.1007/s10822-023-00497-2

Jacob M Remington, Kyle T McKay, Noah B Beckage, Jonathon B Ferrell, Severin T. Schneebeli, Jianing Li

{"title":"GPCRLigNet: rapid screening for GPCR active ligands using machine learning","authors":"Jacob M Remington, Kyle T McKay, Noah B Beckage, Jonathon B Ferrell, Severin T. Schneebeli, Jianing Li","doi":"10.1007/s10822-023-00497-2","DOIUrl":"10.1007/s10822-023-00497-2","url":null,"abstract":"<div><p>Molecules with bioactivity towards G protein-coupled receptors represent a subset of the vast space of small drug-like molecules. Here, we compare machine learning models, including dilated graph convolutional networks, that conduct binary classification to quickly identify molecules with activity towards G protein-coupled receptors. The models are trained and validated using a large set of over 600,000 active, inactive, and decoy compounds. The best performing machine learning model, dubbed GPCRLigNet, was a surprisingly simple feedforward dense neural network mapping from Morgan fingerprints to activity. Incorporation of GPCRLigNet into a high-throughput virtual screening workflow is demonstrated with molecular docking towards a particular G protein-coupled receptor, the pituitary adenylate cyclase-activating polypeptide receptor type 1. Through rigorous comparison of docking scores for molecules selected with and without using GPCRLigNet, we demonstrate an enrichment of potentially potent molecules using GPCRLigNet. This work provides a proof of principle that GPCRLigNet can effectively hone the chemical search space towards ligands with G protein-coupled receptor activity.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 3","pages":"147 - 156"},"PeriodicalIF":3.5,"publicationDate":"2023-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00497-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5331481","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

pH-dependent solubility prediction for optimized drug absorption and compound uptake by plants ph依赖性溶解度预测优化药物吸收和化合物吸收的植物

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-02-17 DOI: 10.1007/s10822-023-00496-3

Anne Bonin, Floriane Montanari, Sebastian Niederführ, Andreas H. Göller

{"title":"pH-dependent solubility prediction for optimized drug absorption and compound uptake by plants","authors":"Anne Bonin, Floriane Montanari, Sebastian Niederführ, Andreas H. Göller","doi":"10.1007/s10822-023-00496-3","DOIUrl":"10.1007/s10822-023-00496-3","url":null,"abstract":"<div><p>Aqueous solubility is the most important physicochemical property for agrochemical and drug candidates and a prerequisite for uptake, distribution, transport, and finally the bioavailability in living species. We here present the first-ever direct machine learning models for pH-dependent solubility in water. For this, we combined almost 300000 data points from 11 solubility assays performed over 24 years and over one million data points from lipophilicity and melting point experiments. Data were split into three pH-classes − acidic, neutral and basic − , representing the conditions of stomach and intestinal tract for animals and humans, and phloem and xylem for plants. We find that multi-task neural networks using ECFP-6 fingerprints outperform baseline random forests and single-task neural networks on the individual tasks. Our final model with three solubility tasks using the pH-class combined data from different assays and five helper tasks results in root mean square errors of 0.56 log units overall (acidic 0.61; neutral 0.52; basic 0.54) and Spearman rank correlations of 0.83 (acidic 0.78; neutral 0.86; basic 0.86), making it a valuable tool for profiling of compounds in pharmaceutical and agrochemical research. The model allows for the prediction of compound pH profiles with mean and median RMSE per molecule of 0.62 and 0.56 log units.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 3","pages":"129 - 145"},"PeriodicalIF":3.5,"publicationDate":"2023-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4680255","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

Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase: molecular docking, in silico toxicity and in vitro experiments 结核分枝杆菌莽草酸激酶潜在抑制剂的鉴定:分子对接、硅毒性和体外实验

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2022-12-22 DOI: 10.1007/s10822-022-00495-w

Talita Freitas de Freitas, Candida Deves Roth, Bruno Lopes Abbadi, Fernanda Souza Macchi Hopf, Marcia Alberton Perelló, Alexia de Matos Czeczot, Eduardo Vieira de Souza, Ana Flávia Borsoi, Pablo Machado, Cristiano Valim Bizarro, Luiz Augusto Basso, Luis Fernando Saraiva Macedo Timmers

{"title":"Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase: molecular docking, in silico toxicity and in vitro experiments","authors":"Talita Freitas de Freitas, Candida Deves Roth, Bruno Lopes Abbadi, Fernanda Souza Macchi Hopf, Marcia Alberton Perelló, Alexia de Matos Czeczot, Eduardo Vieira de Souza, Ana Flávia Borsoi, Pablo Machado, Cristiano Valim Bizarro, Luiz Augusto Basso, Luis Fernando Saraiva Macedo Timmers","doi":"10.1007/s10822-022-00495-w","DOIUrl":"10.1007/s10822-022-00495-w","url":null,"abstract":"<div><p>Tuberculosis (TB) is one of the main causes of death from a single pathological agent, <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of <i>Mtb</i>. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of <i>Mtb</i>. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from <i>Mtb</i> (<i>Mt</i>SK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of <i>Mt</i>SK according to the predicted binding energy. In vitro inhibitory activity of <i>Mt</i>SK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive <i>Mtb</i> H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both <i>Mt</i>SK and the in vitro growth of <i>Mtb</i>.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 3","pages":"117 - 128"},"PeriodicalIF":3.5,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-022-00495-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4848106","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

A combined ligand and target-based virtual screening strategy to repurpose drugs as putrescine uptake inhibitors with trypanocidal activity 结合配体和基于靶标的虚拟筛选策略，重新利用药物作为具有锥虫活性的腐胺摄取抑制剂

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2022-12-10 DOI: 10.1007/s10822-022-00491-0

Manuel A. Llanos, Lucas N. Alberca, María D. Ruiz, María L. Sbaraglini, Cristian Miranda, Agustina Pino-Martinez, Laura Fraccaroli, Carolina Carrillo, Catalina D. Alba Soto, Luciana Gavernet, Alan Talevi

{"title":"A combined ligand and target-based virtual screening strategy to repurpose drugs as putrescine uptake inhibitors with trypanocidal activity","authors":"Manuel A. Llanos, Lucas N. Alberca, María D. Ruiz, María L. Sbaraglini, Cristian Miranda, Agustina Pino-Martinez, Laura Fraccaroli, Carolina Carrillo, Catalina D. Alba Soto, Luciana Gavernet, Alan Talevi","doi":"10.1007/s10822-022-00491-0","DOIUrl":"10.1007/s10822-022-00491-0","url":null,"abstract":"<div><p>Chagas disease, also known as American trypanosomiasis, is a neglected tropical disease caused by the protozoa <i>Trypanosoma cruzi</i>, affecting nearly 7 million people only in the Americas. Polyamines are essential compounds for parasite growth, survival, and differentiation. However, because trypanosomatids are auxotrophic for polyamines, they must be obtained from the host by specific transporters. In this investigation, an ensemble of QSAR classifiers able to identify polyamine analogs with trypanocidal activity was developed. Then, a multi-template homology model of the dimeric polyamine transporter of <i>T. cruzi, Tc</i>PAT12, was created with Rosetta, and then refined by enhanced sampling molecular dynamics simulations. Using representative snapshots extracted from the trajectory, a docking model able to discriminate between active and inactive compounds was developed and validated. Both models were applied in a parallel virtual screening campaign to repurpose known drugs as anti-trypanosomal compounds inhibiting polyamine transport in <i>T. cruzi</i>. Montelukast, Quinestrol, Danazol, and Dutasteride were selected for in vitro testing, and all of them inhibited putrescine uptake in biochemical assays, confirming the predictive ability of the computational models. Furthermore, all the confirmed hits proved to inhibit epimastigote proliferation, and Quinestrol and Danazol were able to inhibit, in the low micromolar range, the viability of trypomastigotes and the intracellular growth of amastigotes.</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 2","pages":"75 - 90"},"PeriodicalIF":3.5,"publicationDate":"2022-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4415472","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: 2

The slow but steady rise of binding free energy calculations in drug discovery 药物发现中结合自由能计算的缓慢而稳定的增长

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2022-12-05 DOI: 10.1007/s10822-022-00494-x

Huafeng Xu

引用次数: 6

DeepCubist: Molecular Generator for Designing Peptidomimetics based on Complex three-dimensional scaffolds DeepCubist:基于复杂三维支架设计肽模拟物的分子生成器

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2022-12-03 DOI: 10.1007/s10822-022-00493-y

Kohei Umedera, Atsushi Yoshimori, Hengwei Chen, Hiroyuki Kouji, Hiroyuki Nakamura, Jürgen Bajorath

引用次数: 1