Journal of Computer-Aided Molecular Design最新文献_第8页

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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

Computational insights into ligand–induced G protein and β-arrestin signaling of the dopamine D1 receptor 配体诱导的G蛋白和多巴胺D1受体的β-阻滞蛋白信号的计算见解

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-04-15 DOI: 10.1007/s10822-023-00503-7

Haoxi Li, Nikhil M. Urs, Nicole Horenstein

{"title":"Computational insights into ligand–induced G protein and β-arrestin signaling of the dopamine D1 receptor","authors":"Haoxi Li, Nikhil M. Urs, Nicole Horenstein","doi":"10.1007/s10822-023-00503-7","DOIUrl":"10.1007/s10822-023-00503-7","url":null,"abstract":"<div><p>The dopamine D1 receptor (D1R), is a class A G protein coupled-receptor (GPCR) which has been a promising drug target for psychiatric and neurological disorders such as Parkinson’s disease (PD). Previous studies have suggested that therapeutic effects can be realized by targeting the β-arrestin signaling pathway of dopamine receptors, while overactivation of the G protein-dependent pathways leads to side effects, such as dyskinesias. Therefore, it is highly desirable to develop a D1R ligand that selectively regulates the β-arrestin pathway. Currently, most D1R agonists are signaling-balanced and stimulate both G protein and β-arrestin pathways, with a few reports of G protein biased ligands. However, identification and characterization of β-arrestin biased D1R agonists has been a challenge thus far. In this study, we implemented Gaussian accelerated molecular dynamics (GaMD) simulations to provide valuable computational insights into the possible underlying molecular mechanism of the different signaling properties of two catechol and two non-catechol D1R agonists that are either G protein biased or signaling-balanced. Dynamic network analysis further identified critical residues in the allosteric signaling network of D1R for each ligand at different conformational or binding states. Some of these residues are crucial for G protein or arrestin signals of GPCRs based on previous studies. Finally, we provided a molecular design strategy which can be utilized by medicinal chemists to develop potential β-arrestin biased D1R ligands. The proposed hypotheses are experimentally testable and can guide the development of safer and more effective medications for a variety of CNS disorders.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4597295","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

Improvement of multi-task learning by data enrichment: application for drug discovery 通过数据充实改进多任务学习:在药物发现中的应用

IF 3.5 3区生物学

Journal of Computer-Aided Molecular Design Pub Date : 2023-03-21 DOI: 10.1007/s10822-023-00500-w

Ekaterina A. Sosnina, Sergey Sosnin, Maxim V. Fedorov

{"title":"Improvement of multi-task learning by data enrichment: application for drug discovery","authors":"Ekaterina A. Sosnina, Sergey Sosnin, Maxim V. Fedorov","doi":"10.1007/s10822-023-00500-w","DOIUrl":"10.1007/s10822-023-00500-w","url":null,"abstract":"<div><p>Multi-task learning in deep neural networks has become a topic of growing importance in many research fields, including drug discovery. However, applying multi-task learning poses new challenges in improving prediction performance. This study investigated the potential of training data enrichment to enhance multi-task model prediction quality in drug discovery. The study evaluated four scenarios with varying degrees of information capacity of the training data and applied two types of test data to evaluate prediction performance. We used three datasets: ViralChEMBL, which consisted of binary activities of compounds against viral species, was applied for the classification task; pQSAR(159) and pQSAR(4267), which consisted of bio-activities of compounds and assays from the research of the profile-QSAR method, were applied for regression tasks. We built multi-task models based on the feed-forward DNNs using the PyTorch framework. Our findings showed that training data enrichment could be an effective means of enhancing prediction performance in multi-task learning, but the degree of improvement depends on the quality of the training data. The more unique compounds and targets the training data included, the more new compound-target interactions are required for prediction improvement. Also, we found out that even using multi-task learning, one could not predict the interactions of compounds that are highly dissimilar from those used for model training. The study provides some recommendations for effectively employing multi-task learning in drug discovery to improve prediction accuracy and facilitate the discovery of novel drug candidates.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4830796","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: 4

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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