Journal of Molecular Recognition最新文献

{"title":"Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon","authors":"Nidhi Sorout,&nbsp;Volkhard Helms","doi":"10.1002/jmr.3108","DOIUrl":"10.1002/jmr.3108","url":null,"abstract":"<p>The Sec61 translocon mediates the translocation of numerous, newly synthesized precursor proteins into the lumen of the endoplasmic reticulum or their integration into its membrane. Recently, structural biology revealed conformations of idle or substrate-engaged Sec61, and likewise its interactions with the accessory membrane proteins Sec62, Sec63, and TRAP, respectively. Several natural and synthetic small molecules have been shown to block Sec61-mediated protein translocation. Since this is a key step in protein biogenesis, broad inhibition is generally cytotoxic, which may be problematic for a putative drug target. Interestingly, several compounds exhibit client-selective modes of action, such that only translocation of certain precursor proteins was affected. Here, we discuss recent advances of structural biology, molecular modelling, and molecular screening that aim to use Sec61 as feasible drug target.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computer-Aided Design of VEGFR-2 Inhibitors as Anticancer Agents: A Review","authors":"Abdullahi Ibrahim Uba","doi":"10.1002/jmr.3104","DOIUrl":"10.1002/jmr.3104","url":null,"abstract":"<div>\u0000 \u0000 <p>Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR-2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR-2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well-tolerated sunitinib and sorafenib, have been approved as VEGFR-2 inhibitors. However, the widespread side effects linked to these VEGFR-2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR-2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer-aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure-based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR-2 inhibitor design. Future VEGFR-2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDR L3 Loop Rearrangement Switches Multispecific SPE-7 IgE Antibody From Hapten to Protein Binding","authors":"Clarissa A. Seidler,&nbsp;Klaus R. Liedl","doi":"10.1002/jmr.3107","DOIUrl":"10.1002/jmr.3107","url":null,"abstract":"<p>The monoclonal IgE antibody SPE-7 was originally raised against a 2,4-dinitrophenyl (DNP) target. Through its ability to adopt multiple conformations, the antibody is capable of binding to a diverse range of small haptens and large proteins. The present study examines a dataset of experimentally determined crystal structures of the SPE-7 antibody to gain insight into the mechanisms that contribute to its multispecificity. With the emergence of more and more therapeutic antibodies against a huge repertoire of different targets, our research could be of great interest for future drug development. We are able to discriminate between the different paratope-binding states in the conformational ensembles obtained by enhanced sampling molecular dynamics simulations, and to calculate their transition timescales and state probabilities. Furthermore, we describe the key residues responsible for discriminating between the different binding capacities and identify a tryptophan in a central position of the CDR L3 loop as the residue of greatest interest. The overall dynamics of the paratope appear to be mainly influenced by the CDR L3 and CDR L1 loops.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 6","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmr.3107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspectives Toward an Integrative Structural Biology Pipeline With Atomic Force Microscopy Topographic Images","authors":"Jean-Luc Pellequer","doi":"10.1002/jmr.3102","DOIUrl":"10.1002/jmr.3102","url":null,"abstract":"<p>After the recent double revolutions in structural biology, which include the use of direct detectors for cryo-electron microscopy resulting in a significant improvement in the expected resolution of large macromolecule structures, and the advent of AlphaFold which allows for near-accurate prediction of any protein structures, the field of structural biology is now pursuing more ambitious targets, including several MDa assemblies. But complex target systems cannot be tackled using a single biophysical technique. The field of integrative structural biology has emerged as a global solution. The aim is to integrate data from multiple complementary techniques to produce a final three-dimensional model that cannot be obtained from any single technique. The absence of atomic force microscopy data from integrative structural biology platforms is not necessarily due to its nm resolution, as opposed to Å resolution for x-ray crystallography, nuclear magnetic resonance, or electron microscopy. Rather a significant issue was that the AFM topographic data lacked interpretability. Fortunately, with the introduction of the AFM-Assembly pipeline and other similar tools, it is now possible to integrate AFM topographic data into integrative modeling platforms. The advantages of single molecule techniques, such as AFM, include the ability to confirm experimentally any assembled molecular models or to produce alternative conformations that mimic the inherent flexibility of large proteins or complexes. The review begins with a brief overview of the historical developments of AFM data in structural biology, followed by an examination of the strengths and limitations of AFM imaging, which have hindered its integration into modern modeling platforms. This review discusses the correction and improvement of AFM topographic images, as well as the principles behind the AFM-Assembly pipeline. It also presents and discusses a series of challenges that need to be addressed in order to improve the incorporation of AFM data into integrative modeling platform.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 6","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmr.3102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microsecond Molecular Dynamics Simulation to Gain Insight Into the Binding of MRTX1133 and Trametinib With KRASG12D Mutant Protein for Drug Repurposing","authors":"Iruthayaraj Ancy,&nbsp;Sakayanathan Penislusshiyan,&nbsp;Fuad Ameen,&nbsp;Loganathan Chitra","doi":"10.1002/jmr.3103","DOIUrl":"10.1002/jmr.3103","url":null,"abstract":"<div>\u0000 \u0000 <p>The Kirsten Rat Sarcoma (KRAS) G12D mutant protein is a primary driver of pancreatic ductal adenocarcinoma, necessitating the identification of targeted drug molecules. Repurposing of drugs quickly finds new uses, speeding treatment development. This study employs microsecond molecular dynamics simulations to unveil the binding mechanisms of the FDA-approved MEK inhibitor trametinib with KRAS^G12D, providing insights for potential drug repurposing. The binding of trametinib was compared with clinical trial drug MRTX1133, which demonstrates exceptional activity against KRAS^G12D, for better understanding of interaction mechanism of trametinib with KRAS^G12D. The resulting stable MRTX1133-KRAS^G12D complex reduces root mean square deviation (RMSD) values, in Switch I and II domains, highlighting its potential for inhibiting KRAS^G12D. MRTX1133's robust interaction with Tyr64 and disruption of Tyr96-Tyr71-Arg68 network showcase its ability to mitigate the effects of the G12D mutation. In contrast, trametinib employs a distinctive binding mechanism involving P-loop, Switch I and II residues. Extended simulations to 1 μs reveal sustained network interactions with Tyr32, Thr58, and GDP, suggesting a role of trametinib in maintaining KRAS^G12D in an inactive state and impede the further cell signaling. The decomposition binding free energy values illustrate amino acids' contributions to binding energy, elucidating ligand–protein interactions and molecular stability. The machine learning approach reveals that van der Waals interactions among the residues play vital role in complex stability and the potential amino acids involved in drug–receptor interactions of each complex. These details provide a molecular-level understanding of drug binding mechanisms, offering essential knowledge for further drug repurposing and potential drug discovery.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 6","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Analysis of Interactions Between Drugs and Human Serum Albumin","authors":"Muslum Yildiz","doi":"10.1002/jmr.3105","DOIUrl":"10.1002/jmr.3105","url":null,"abstract":"<p>Drug molecules exist as complexed with serum proteins such as human serum albumin (HSA) and/or unbound free form in the blood circulation. Drugs can be effective only when they are free. Thus, it is important to understand aspects that are important for interaction between drugs and interacting proteins. In this study, interactions among 2990 FDA approved drugs and HSA were computational analyzed to unravel principles that are critical for drug-HSA interactions. Docking results showed that drugs have higher affinity toward cavity-1 (C1) than cavity-2 (C2). A total of 1131 drug molecules have docking score greater than 60 while 768 molecules have docking score greater than 60 when they are docked in C2. In addition, three solvent channels have potential to direct solvent to C1 cavity while C2 does not have any effective channel. The post MD analyses demonstrated that drugs are making polar interactions with basic amino acids in the binding cavities. Verbscoside and ceftazidime both have stable low RMSD values throughout MD simulation with 2 Å on average in C1 cavity. The ligand RMSD shows less stability for verbscoside, which is around 4 Å when it is in complex with HSA in C1. The individual contribution of the residues K192, K196, R215, and R254 to ceftazidime are −1.92 ± 0.18, −3.09 ± 0.09, −2.17 ± 0.17, and − 2.32 ± 0.098, respectively. These residues contribute the binding energy of the verbscoside by −6.06 ± 0.08, −2.10 ± 0.06, and − 1.57 ± 0.03 kcal/mol individually in C1 cavity. C2 is making polar interactions with drug via R469, K472, and K488 residues and their contribution to the two drugs are −3.13 ± 0.21 kcal/mol for R469, −1.94 ± 0.18 kcal/mol for K472, and −1.96 ± 0.11 kcal/mol for K488 to total binding energy of ceftazidime. The binding energy of verbscoside is 57.17 ± 7.00 kcal/mol and Arg-407 has the highest contribution this bind energy individually with −4.29 ± 0.12 kcal/mol. Drugs with hydrogen bond donor/acceptor chemical adducts such as verbscoside involve higher hydrogen bond formation in C1 pocket. Ceftazidime makes interaction with HSA toward hydrophobic residues, L384, L404, L487, and L488 in the C2 cavity.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 6","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmr.3105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Inhibition of Diindolylmethane Derivatives on SARS-CoV-2 Main Protease","authors":"Wenjin Li,&nbsp;Xiaoyu Chang,&nbsp;Hang Zhou,&nbsp;Wenquan Yu,&nbsp;Ruiyong Wang,&nbsp;Junbiao Chang","doi":"10.1002/jmr.3101","DOIUrl":"10.1002/jmr.3101","url":null,"abstract":"<div>\u0000 \u0000 <p>The SARS-CoV-2 main protease (Mpro) is an essential enzyme that promotes viral transcription and replication. Mpro conserved nature in different variants and its nonoverlapping nature with human proteases make it an attractive target for therapeutic intervention against SARS-CoV-2. In this work, the interaction mechanism between Mpro and diindolylmethane derivatives was investigated by molecular docking, enzymatic inhibition assay, UV–vis, fluorescence spectroscopy, and circular dichroism spectroscopy. Results of IC₅₀ values show that <b>1p</b> (9.87 μM) was the strongest inhibitor for Mpro in this work, which significantly inhibited the activity of Mpro. The binding constant (4.07 × 10⁵ Lmol⁻¹), the quenching constant (5.41 × 10⁵ Lmol⁻¹), and thermodynamic parameters indicated that the quenching mode of <b>1p</b> was static quenching, and the main driving forces between <b>1p</b> and Mpro are hydrogen bond and van der Waals force. The influence of molecular structure on the binding is investigated. Chlorine atoms and methoxy groups are favorable for the diindolylmethane derivative inhibitors of Mpro. This work confirms the changes in the microenvironment of Mpro by <b>1p</b>, and provides clues for the design of potential inhibitors.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 6","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing the interaction between the metallo-β-lactamase SMB-1 and ampicillin by multispectral approaches combined with molecular dynamics","authors":"Jiachen Li,&nbsp;Xiaoting Dong,&nbsp;Yeli Zhang","doi":"10.1002/jmr.3100","DOIUrl":"10.1002/jmr.3100","url":null,"abstract":"<p>Metallo-β-lactamases (MβLs) hydrolyze and inactivate β-lactam antibiotics, are a pivotal mechanism conferring resistance against bacterial infections. SMB-1, a novel B3 subclass of MβLs from <i>Serratia marcescens</i> could deactivate almost all β-lactam antibiotics including ampicillin (AMP), which has posed a serious threat to public health. To illuminate the mechanism of recognition and interaction between SMB-1 and AMP, various fluorescence spectroscopy techniques and molecular dynamics simulation were employed. The results of quenching spectroscopy unraveled that AMP could make SMB-1 fluorescence quenching that mechanism was the static quenching; the synchronous and three-dimensional fluorescence spectra validated that the microenvironment and conformation of SMB-1 were altered after interaction with AMP. The molecular dynamics results demonstrated that the whole AMP enters the binding pocket of SMB-1, even though with a relatively bulky R1 side chain. Loop1 and loop2 in SMB-1 undergo significant fluctuations, and α2 (71–73) and local α5 (186–188) were turned into random coils, promoting zinc ion exposure consistent with circular dichroism spectroscopy results. The binding between them was driven by a combination of enthalpy and entropy changes, which was dominated by electrostatic force in agreement with the fluorescence observations. The present study brings structural insights and solid foundations for the design of new substrates for β-lactamases and the development of effective antibiotics that are resistant to superbugs.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding characteristics of the doxepin E/Z-isomers to the histamine H1 receptor revealed by receptor-bound ligand analysis and molecular dynamics study","authors":"Hiroto Kaneko,&nbsp;Ryunosuke Korenaga,&nbsp;Ryota Nakamura,&nbsp;Shinnosuke Kawai,&nbsp;Tadashi Ando,&nbsp;Mitsunori Shiroishi","doi":"10.1002/jmr.3098","DOIUrl":"10.1002/jmr.3098","url":null,"abstract":"<p>Doxepin is an antihistamine and tricyclic antidepressant that binds to the histamine H₁ receptor (H₁R) with high affinity. Doxepin is an 85:15 mixture of the E- and Z-isomers. The Z-isomer is well known to be more effective than the E-isomer, whereas based on the crystal structure of the H₁R/doxepin complex, the hydroxyl group of Thr112^3.37 is close enough to form a hydrogen bond with the oxygen atom of the E-isomer. The detailed binding characteristics and reasons for the differences remain unclear. In this study, we analyzed doxepin isomers bound to the receptor following extraction from a purified H₁R protein complexed with doxepin. The ratio of the E- and Z-isomers bound to wild-type (WT) H₁R was 55:45, indicating that the Z-isomer was bound to WT H₁R with an approximately 5.2-fold higher affinity than the E-isomer. For the T112^3.37V mutant, the E/Z ratio was 89:11, indicating that both isomers have similar affinities. Free energy calculations using molecular dynamics (MD) simulations also reproduced the experimental results of the relative binding free energy differences between the isomers for WT and T112^3.37V. Furthermore, MD simulations revealed that the hydroxyl group of T112^3.37 did not form hydrogen bonds with the E-isomer, but with the adjacent residues in the binding pocket. Analysis of the receptor-bound doxepin and MD simulations suggested that the hydroxyl group of T112^3.37 contributes to the formation of a chemical environment in the binding pocket, which is slightly more favorable for the Z-isomer without hydrogen bonding with doxepin.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmr.3098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurement of protein concentration in bacteria and small organelles under a light transmission microscope","authors":"M. A. Model,&nbsp;R. Guo,&nbsp;K. Fasina,&nbsp;R. Jin,&nbsp;R. J. Clements,&nbsp;L. G. Leff","doi":"10.1002/jmr.3099","DOIUrl":"10.1002/jmr.3099","url":null,"abstract":"<p>Protein concentration (PC) is an essential characteristic of cells and organelles; it determines the extent of macromolecular crowding effects and serves as a sensitive indicator of cellular health. A simple and direct way to quantify PC is provided by brightfield-based transport-of-intensity equation (TIE) imaging combined with volume measurements. However, since TIE is based on geometric optics, its applicability to micrometer-sized particles is not clear. Here, we show that TIE can be used on particles with sizes comparable to the wavelength. At the same time, we introduce a new ImageJ plugin that allows TIE image processing without resorting to advanced mathematical programs. To convert TIE data to PC, knowledge of particle volumes is essential. The volumes of bacteria or other isolated particles can be measured by displacement of an external absorbing dye (“transmission-through-dye” or TTD microscopy), and for spherical intracellular particles, volumes can be estimated from their diameters. We illustrate the use of TIE on <i>Escherichia coli</i>, mammalian nucleoli, and nucleolar fibrillar centers. The method is easy to use and achieves high spatial resolution.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmr.3099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}