Journal of Molecular Recognition最新文献

{"title":"Dissecting the COVID-19 Immune Response: Unraveling the Pathways of Innate Sensing and Response to SARS-CoV-2 Structural Proteins","authors":"Matheus de Oliveira Silva Pinto,&nbsp;Leonardo de Paula Pereira,&nbsp;Ana Luiza Pessoa de Mendonça Angelo,&nbsp;Marcelo Antônio Pascoal Xavier,&nbsp;Alexandre de Magalhães Vieira Machado,&nbsp;Remo Castro Russo","doi":"10.1002/jmr.70002","DOIUrl":"https://doi.org/10.1002/jmr.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>Severe acute respiratory syndrome coronavirus (SARS-CoV), the virus responsible for COVID-19, interacts with the host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining the disease's severity and the host's ability to clear the virus. Given the virus's substantial socioeconomic impact, high morbidity and mortality rates, and public health importance, understanding these mechanisms is essential. This article examines the diverse innate immune responses triggered by SARS-CoV-2's structural proteins, including the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins, along with nonstructural proteins (NSPs) and open reading frames. These proteins play pivotal roles in immune modulation, facilitating viral replication, evading immune detection, and contributing to severe inflammatory responses such as cytokine storms and acute respiratory distress syndrome (ARDS). The virus employs strategies like suppressing type I interferon production and disrupting key antiviral pathways, including MAVS, OAS-RNase-L, and PKR. This study also explores the immune pathways that govern the activation and suppression of immune responses throughout COVID-19. By analyzing immune sensing receptors and the responses initiated upon recognizing SARS-CoV-2 structural proteins, this review elucidates the complex pathways associated with the innate immune response in COVID-19. Understanding these mechanisms offers valuable insights for therapeutic interventions and informs public health strategies, contributing to a deeper understanding of COVID-19 immunopathogenesis.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 2","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112377","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":"Inhibitory Potential and Binding Thermodynamics of Scyllatoxin-Based BH3 Domain Mimetics Targeting Repressor BCL2 Proteins","authors":"H. A. D. B. Amarasiri,&nbsp;Danushka Arachchige,&nbsp;Matthew J. K. Vince,&nbsp;Justin M. Holub","doi":"10.1002/jmr.70001","DOIUrl":"https://doi.org/10.1002/jmr.70001","url":null,"abstract":"<p>The B-cell lymphoma 2 (BCL2) proteins are a class of apoptosis regulators that control the release of apoptogenic factors from mitochondria. Under normal physiological conditions, apoptosis is inhibited through the actions of anti-apoptotic (repressor) BCL2 proteins that bind semi-indiscriminately to the helical BH3 domains of pro-apoptotic (effector) BCL2 proteins. In this work, we developed a series of BH3 domain mimetics by grafting residues from the effector BCL2 protein Bax onto the α-helix of scyllatoxin (ScTx). These so-called “ScTx-Bax” constructs were then used to gain insight into the physicochemical nature of repressor/effector BCL2 interactions. Specifically, we utilized competitive binding and isothermal titration calorimetry (ITC) to investigate the inhibitory potential and binding thermodynamics of ScTx-Bax structural variants that target the repressor protein Bcl-2 (proper) in vitro. Our data show that ScTx-Bax mimetics compete with isolated Bax BH3 domain peptides for Bcl-2 with IC₅₀ values in the mid-nanomolar range and that greater flexibility within the ScTx-Bax BH3 domain correlates with more effective inhibition. Furthermore, ITC experiments revealed that unstructured ScTx-Bax variants target Bcl-2 with greater entropic, but lower enthalpic, efficiencies than structured ScTx-Bax peptides. These results suggest that entropic contributions to binding Bcl-2 are more favorable for flexible BH3 domains; however, this enhancement is counterbalanced by a moderate enthalpic penalty. Overall, this study improves understanding of how structural properties of effector BH3 domains influence the promiscuous binding patterns of BCL2 proteins and expands the utility of ScTx-based BH3 domain mimetics as molecular tools to study discrete recognition elements that facilitate repressor/effector BCL2 interactions.</p>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 2","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmr.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111626","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":"A Serum D-Fucose Binding Lectin With B Cell Mitogenic Activity From the Grub of the Darkling Beetle Zophobas morio","authors":"Ramanathan Nivetha,&nbsp;Mani Meenakumari,&nbsp;Sreeramulu Bhuvaragavan,&nbsp;Ayikkara Peroor Mahi Dev,&nbsp;Sundaram Janarthanan","doi":"10.1002/jmr.70000","DOIUrl":"10.1002/jmr.70000","url":null,"abstract":"<div>\u0000 \u0000 <p>Lectins that can recognize and bind to carbohydrates and glycoconjugates are at the epicentre of research owing to their prospective applications. In the present study, a D-fucose binding lectin from the serum of darkling beetle, <i>Zophobas morio</i> was purified and their mitogenic potential over human B-cells was evaluated. Biochemical assays on the preliminary characterization revealed the occurrence of single D-fucose binding lectin. Through single step affinity chromatography using D-fucose coupled Epoxy-activated Sepharose 6B, lectin (<i>Zm</i>FBL) with a molecular mass of ~192 kDa from the serum of <i>Z</i>. <i>morio</i> was purified with homogeneity. The HA activity of the purified <i>Zm</i>FBL remained stable between the pH 7 and 12 and was thermo-tolerant up to a temperature of 40°C. MALDI-TOF-MS analysis of native lectin disclosed fucose-binding nature of the <i>Zm</i>FBL with mitogenic property. The results of functional analysis of purified <i>Zm</i>FBL on the effect on B-cell proliferation revealed that <i>Zm</i>FBL at the concentrations of 31.25 μg and 62.50 were the ideal concentrations that significantly enhanced (approximately 2.5-fold over control) the proliferation of the B-lymphocyte population up to 72 h of treatment without any cytotoxicity. The outcome of this study could possibly prove beneficial in the investigation on the potential use of <i>Zm</i>FBL as immunostimulant and in immunosuppressive treatments.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007045","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":"Deciphering Saquinavir–Bovine Serum Albumin Interactions: Spectroscopic and Computational Insights","authors":"Vijayakumar Rajendran,&nbsp;Saravanan Kandasamy,&nbsp;Seshan Gunalan,&nbsp;Sekar Kanagaraj,&nbsp;Gugan Kothandan","doi":"10.1002/jmr.3112","DOIUrl":"10.1002/jmr.3112","url":null,"abstract":"<div>\u0000 \u0000 <p>Bovine serum albumin (BSA) plays a crucial role as a carrier protein in plasma, binding various ligands, including drugs. Understanding the interaction between BSA and saquinavir, an antiretroviral drug, is essential for predicting its pharmacokinetics and pharmacodynamics. We employed spectroscopic approaches, including circular dichroism spectrometry and fluorescence spectroscopy, to investigate the binding of saquinavir to BSA. CD studies revealed conformational changes upon saquinavir mesylate binding, and the complex was stable up to 45°C during thermal denaturation. Saquinavir quenched the intrinsic fluorescence of BSA, indicating static quenching due to complex formation. Additionally, molecular docking simulations were performed to elucidate the favored binding site and interactions. The molecular docking results revealed that Subdomains IIA and IIB, which are proximal to Sudlow Site I, are the principal binding sites for the antiviral drug saquinavir. The ligand-bound pose of BSA also revealed that residue Trp213, which is adjacent to saquinavir, further validated the results of the fluorescence quenching assay, suggesting that residue Trp213 is quenched upon binding with saquinavir. MD simulations allowed us to explore the dynamic behavior of the BSA–saquinavir complex over time. We observed conformational fluctuations, solvent exposure, flexibility of binding pockets, free energy landscape, and binding energy. This study enhances our understanding of drug–protein interactions and contributes to drug development and optimization.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921847","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":"TAZ-hTrap: A Rationally Designed, Disulfide-Stapled Tead Helical Hairpin Trap to Selectively Capture Hippo Signaling Taz With Potent Antigynecological Tumor Activity","authors":"Bin Tang,&nbsp;Yu Du,&nbsp;Jun Wang","doi":"10.1002/jmr.3111","DOIUrl":"10.1002/jmr.3111","url":null,"abstract":"<div>\u0000 \u0000 <p>Transcriptional enhanced associate domain (Tead)–mediated Hippo signaling pathway regulates diverse physiological processes; its dysfunction has been implicated in an increasing number of human gynecological cancers. The transcriptional coactivator with PDZ-binding motif (Taz) binds to and then activates Tead through forming a three-helix bundle (THB) at their complex interface. The THB is defined by a double-helical hairpin from Tead and a single α-helix from Taz, serving as the key interaction hotspot between Tead and Taz. In the present study, the helical hairpin was derived from Tead protein to generate a hairpin segment, which is a 25-mer polypeptide consisting of a longer helical arm-1 and a shorter helical arm-2 as well as a flexible loop linker between them. Dynamics simulation and energetics characterization revealed that the hairpin peptide is intrinsically disordered when splitting from its protein context, thus incurring a large entropy penalty upon binding to Taz α-helix. A disulfide bridge was introduced across the two helical arms of hairpin peptide to obtain a strong binder termed TAZ-hTrap, which can maintain in a considerably structured, native-like conformation in unbound state, and the entropy penalty was minimized by disulfide stapling to effectively improve its affinity toward the α-helix. These computational findings can be further substantiated by circular dichroism and fluorescence polarization at molecular level, and viability assay also observed a potent cytotoxic effect on diverse human gynecological tumors at cellular level. In addition, we further demonstrated that the TAZ-hTrap has a good selectivity for its cognate Taz over other noncognate proteins that share a high conservation with the Taz α-helix.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 2","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769848","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 Molecular Basis of Aminoacyl-Adenylate Affinity With Mycobacterium tuberculosis Leucyl-tRNA Synthetase Employing Molecular Dynamics, Umbrella Sampling Simulations and Site-Directed Mutagenesis","authors":"Galyna P. Volynets,&nbsp;Olga I. Gudzera,&nbsp;Mariia O. Usenko,&nbsp;Oksana B. Gorbatiuk,&nbsp;Volodymyr G. Bdzhola,&nbsp;Igor M. Kotey,&nbsp;Anatoliy O. Balanda,&nbsp;Andrii O. Prykhod'ko,&nbsp;Sergiy S. Lukashov,&nbsp;Oleksiy A. Chuk,&nbsp;Oleksandra I. Skydanovych,&nbsp;Ganna D. Yaremchuk,&nbsp;Sergiy M. Yarmoluk,&nbsp;Michael A. Tukalo","doi":"10.1002/jmr.3110","DOIUrl":"10.1002/jmr.3110","url":null,"abstract":"<div>\u0000 \u0000 <p>Leucyl-tRNA synthetase (LeuRS) is clinically validated molecular target for antibiotic development. Recently, we have reported several classes of small-molecular inhibitors targeting aminoacyl-adenylate binding site of <i>Mycobacterium tuberculosis</i> LeuRS with antibacterial activity. In this work, we performed in silico site-directed mutagenesis of <i>M. tuberculosis</i> LeuRS synthetic site in order to identify the most critical amino acid residues for the interaction with substrate and prove binding modes of inhibitors. We carried out 20-ns molecular dynamics (MD) simulations and used umbrella sampling (US) method for the calculation of the binding free energy (ΔGb) of leucyl-adenylate with wild-type and mutated forms of LeuRS. According to molecular modeling results, it was found that His89, Tyr93, and Glu660 are essential amino acid residues both for aminoacyl-adenylate affinity and hydrogen bond formation. We have selected His89 for experimental site-directed mutagenesis since according to our previous molecular docking results this amino acid residue was predicted to be important for inhibitor interaction in adenine-binding region. We obtained recombinant mutant <i>M. tuberculosis</i> LeuRS H89A. Using aminoacylation assay we have found that the mutation of His89 to Ala in the active site of <i>M. tuberculosis</i> LeuRS results in significant decrease of inhibitory activity for compounds belonging to three different chemical classes—3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazoles, <i>N</i>-benzylidene-<i>N</i>′-thiazol-2-yl-hydrazines, and 1-oxo-1H-isothiochromene-3-carboxylic acid (4-phenyl-thiazol-2-yl)-amide derivatives. Therefore, the interaction with His89 should be taken into account during further <i>M. tuberculosis</i> LeuRS inhibitors development and optimization.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 2","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546007","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":"Role of Circular RNA MMP9 in Glioblastoma Progression: From Interaction With hnRNPC and hnRNPA1 to Affecting the Expression of BIRC5 by Sequestering miR-149","authors":"Javad Amini,&nbsp;Nikta Zafarjafarzadeh,&nbsp;Sara Ghahramanlu,&nbsp;Omid Mohammadalizadeh,&nbsp;Elaheh Mozaffari,&nbsp;Bahram Bibak,&nbsp;Nima Sanadgol","doi":"10.1002/jmr.3109","DOIUrl":"10.1002/jmr.3109","url":null,"abstract":"<div>\u0000 \u0000 <p>Glioblastoma multiforme (GBM) presents a significant challenge in neuro-oncology due to its aggressive behavior and self-renewal capacity. Circular RNAs (circRNAs), a subset of non-coding RNAs (ncRNAs) generated through mRNA back-splicing, are gaining attention as potential targets for GBM research. In our study, we sought to explore the functional role of circMMP9 (circular form of matrix metalloproteinase-9) as a promising therapeutic target for GBM through bioinformatic predictions and human data analysis. Our results suggest that circMMP9 functions as a sponge for miR-149 and miR-542, both upregulated in GBM based on microarray data. Kaplan–Meier analysis indicated that reduced levels of miR-149 and miR-542 correlate with worse survival outcomes in GBM, suggesting their role as tumor suppressors. Importantly, miR-149 has been demonstrated to inhibit the expression of BIRC5 (baculoviral inhibitor of apoptosis repeat-containing 5 or survivin), a significant promoter of proliferation in GBM. BIRC5 is not only upregulated in GBM but also in various other cancers, including neuroblastoma and other brain cancers. Our protein–protein interaction analysis highlights the significance of BIRC5 as a central hub gene in GBM. CircMMP9 seems to influence this complex relationship by suppressing miR-149 and miR-542, despite their increased expression in GBM. Additionally, we found that circMMP9 directly interacts with heterogeneous nuclear ribonucleoproteins C and A1 (hnRNPC and A1), although not within their protein-binding domains. This suggests that hnRNPC/A1 may play a role in transporting circMMP9. Moreover, RNA-seq data from GBM patient samples confirmed the increased expression of BIRC5, PIK3CB, and hnRNPC/A1, further emphasizing the potential therapeutic significance of circMMP9 in GBM. In this study, we propose for the first time a new epigenetic regulatory role for circMMP9, highlighting a novel aspect of its oncogenic function. circMMP9 may regulate BIRC5 expression in GBM by sponging miR-149 and miR-542. BIRC5, in turn, suppresses apoptosis and enhances proliferation in GBM. Nonetheless, more extensive studies are advised to delve deeper into the roles of circMMP9, especially in the context of glioma.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467947","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":"Targeting Human Papillomavirus 33 E2 DNA Binding Domain With Polyphenols: Unveiling Interactions Through Biophysical and In Silico Methods","authors":"Bharti,&nbsp;Maya S. Nair","doi":"10.1002/jmr.3106","DOIUrl":"10.1002/jmr.3106","url":null,"abstract":"<div>\u0000 \u0000 <p>The human papillomavirus (HPV) 33 is a high-risk strain that causes lesions with potential cancerous outcomes. Its E2 protein regulates the viral protein transcription and life cycle maintenance. The DNA binding domain (DBD) of the E2 protein plays a crucial role in the viral life cycle. The DBD region of the E2 protein is particularly interesting for targeting and finding potential inhibitors to inhibit its function or dimerization. Given the limited research on HPV 33 and its proteins, the present work delved into the interaction of two natural polyphenolic compounds, resveratrol, and baicalein, with the E2 DBD of HPV 33 using biophysical and in silico studies. Fluorescence studies of the E2 DBD-polyphenol complexes showed fluorescence quenching with a binding constant of the order of 10⁶ M⁻¹. Circular dichroism data reveal conformational changes upon binding with the polyphenols, possibly due to distinct binding sites of the E2 DBD. Differential scanning calorimetry exhibited higher melting temperatures for the two complexes than alone DBD, suggesting the complexes' stability. ITC experiment suggested favorable binding reactions with <i>k</i>\u0000 _{\u0000 <i>d</i>\u0000} values in the micromolar range. Molecular docking and dynamic simulation studies revealed that the resveratrol binds to the helical region and baicalein near the central dimeric interface of E2 DBD with a good binding affinity, forming a stable protein-ligand complex during the run of 100 ns simulation. Therefore, the current study identifies both polyphenolic compounds as promising candidates for potential antiviral drug development.</p>\u0000 </div>","PeriodicalId":16531,"journal":{"name":"Journal of Molecular Recognition","volume":"38 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467948","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":"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}