Journal of Molecular Recognition最新文献

{"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}

{"title":"Synthesis, molecular dynamics simulation, and evaluation of biological activity of novel flurbiprofen and ibuprofen-like compounds","authors":"Mehmet Taha Yıldız,&nbsp;Derya Osmaniye,&nbsp;Begum Nurpelin Saglik,&nbsp;Serkan Levent,&nbsp;Recep Kurnaz,&nbsp;Yusuf Ozkay,&nbsp;Zafer Asım Kaplancıklı","doi":"10.1002/jmr.3089","DOIUrl":"10.1002/jmr.3089","url":null,"abstract":"<p>The frequent use of anti-inflammatory drugs and the side effects of existing drugs keep the need for new compounds constant. For this purpose, flurbiprofen and ibuprofen-like compounds, which are frequently used anti-inflammatory compounds in this study, were synthesized and their structures were elucidated. Like ibuprofen and flurbiprofen, the compounds contain a residue of phenylacetic acid. On the other hand, it contains a secondary amine residue. Thus, it is planned to reduce the acidity, which is the biggest side effect of NSAI drugs, even a little bit. The estimated ADME parameters of the compounds were evaluated. Apart from internal use, local use of anti-inflammatory compounds is also very important. For this reason, the skin permeability values of the compounds were also calculated. And it has been found to be compatible with reference drugs. The COX enzyme inhibitory effects of the obtained compounds were tested by in vitro experiments. Compound <b>2a</b> showed significant activity against COX-1 enzyme with an IC₅₀ = 0.123 + 0.005 μM. The interaction of the compound with the enzyme active site was clarified by molecular dynamics studies.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419579","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":"Identification of DPP-IV inhibitory peptides derived from buffalo colostrum: Mining through bioinformatics, in silico and in vitro approaches","authors":"Arpitha Ashok,&nbsp;Aparna H. S.","doi":"10.1002/jmr.3090","DOIUrl":"10.1002/jmr.3090","url":null,"abstract":"<p>Bioactive peptides derived from foods provide physiological health benefits beyond nutrition. This study focused on profiling small peptide inhibitors against two key serine proteases, dipeptidyl peptidase-IV (DPP-IV) and prolyl oligopeptidase (POP). DPP-IV is a well-known protein involved in diverse pathways regulating inflammation, renal, cardiovascular physiology, and glucose homeostasis. POP is yet another key target protein for neurodegenerative disorders. The study evaluated peptide libraries of buffalo colostrum whey and fat globule membrane proteins derived from pepsin and pepsin–pancreatin digestion through in silico web tools and structure-based analysis by molecular docking and binding free-energy estimation, followed by in vitro assay for DPP-IV inhibition for the lead peptides. The bioinformatic study indicated 49 peptides presented motifs with DPP-IV inhibition while 5 peptides with sequences for POP inhibition. In the molecular docking interactions study, 22 peptides interacted with active site residues of DPP-IV and 3 peptides with that of POP. The synthesized peptides, SFVSEVPEL and LTFQHNF inhibited DPP-IV in vitro with an IC50 of 193.5 μM and 1.782 mM, respectively. The study revealed the key residues for inhibition of DPP-IV and POP thus affirming the DPP-IV inhibitory potential of milk-derived peptides.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158512","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":"Nanomechanical collective vibration of SARS-CoV-2 spike proteins","authors":"Changfeng Cao,&nbsp;Guangxu Zhang,&nbsp;Xueling Li,&nbsp;Yadi Wang,&nbsp;Junhong Lü","doi":"10.1002/jmr.3091","DOIUrl":"10.1002/jmr.3091","url":null,"abstract":"<p>The development of effective therapeutics against COVID-19 requires a thorough understanding of the receptor recognition mechanism of the SARS-CoV-2 spike (S) protein. Here the multidomain collective dynamics on the trimer of the spike protein has been analyzed using normal mode analysis (NMA). A common nanomechanical profile was identified in the spike proteins of SARS-CoV-2 and its variants. The profile involves collective vibrations of the receptor-binding domain (RBD) and the N-terminal domain (NTD), which may mediate the physical interaction process. Quantitative analysis of the collective modes suggests a nanomechanical property involving large-scale conformational changes, which explains the difference in receptor binding affinity among different variants. These results support the use of intrinsic global dynamics as a valuable perspective for studying the allosteric and functional mechanisms of the S protein. This approach also provides a low-cost theoretical toolkit for screening potential pathogenic mutations and drug targets.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076085","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":"A versatile ratiometric fluorescence nanoprobe for the determination of clonazepam in patients' plasma samples","authors":"Mohammad Abbasi,&nbsp;Abolghasem Jouyban,&nbsp;Fatemeh Ranjbar,&nbsp;Jafar Soleymani","doi":"10.1002/jmr.3088","DOIUrl":"10.1002/jmr.3088","url":null,"abstract":"<p>Despite the necessity of the study of therapeutic drug monitoring of clonazepam (CLZ), there are only a few fast detection methods available for determining CLZ in biological media. This study aims to develop a cost-effective and ratiometric probe for the quantification of CLZ in plasma samples. Fluorescent polydopamine nanoparticles were produced through a self-polymerization process at a pH of 8.5. Rhodamine B molecules were employed as a fluorescent reference material, emitting stable fluorescence in the visible range. The fabricated probe exhibited a specific detection capability for CLZ. The fluorescence emission of the probe was enhanced in two concentration ranges: from 50 ng/mL to 1.0 μg/mL and from 1.0 to 15.0 μg/mL with a lower limit of quantification of 50 ng/mL, indicating the sensitivity of the probe for detecting CLZ plasma levels. The accuracy of the probe is favorable which could be recommended for CLZ monitoring in the biological media. Furthermore, this probe is highly specific towards CLZ in the presence of various interfering agents which is mainly caused by its ratiometric nature. The developed platform showed high reliability in quantifying CLZ concentrations in patients' plasma samples. Hence, the fabricated probe could be recommended as a reliable method for the routine detection of CLZ in clinical settings.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"37 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957937","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}