Journal of Biomolecular Structure & Dynamics最新文献

{"title":"Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer.","authors":"Pooja Maurya, Rohit Singh Rawat, Sampa Gupta, Shagun Krishna, Mohammad Imran Siddiqi, Koneni V Sashidhara, Dibyendu Banerjee","doi":"10.1080/07391102.2023.2297817","DOIUrl":"10.1080/07391102.2023.2297817","url":null,"abstract":"<p><p>DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal cancer cells. Notably, cells with downregulated hLig I (<i>via</i> siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3390-3405"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139097856","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}

{"title":"Molecular docking and dynamics simulations revealed the potential inhibitory activity of honey-iQfood ingredients against GSK-3β and CDK5 protein targets for brain health.","authors":"Nor Hafizah Zakaria, Fatahiya Mohamed Tap, Ghadah Faraj Aljohani, Fadzilah Adibah Abdul Majid","doi":"10.1080/07391102.2023.2298726","DOIUrl":"10.1080/07391102.2023.2298726","url":null,"abstract":"<p><p>Honey-iQfood is an herbal supplement made of a mixture of polyherbal extracts and wild honey. The mixture is traditionally claimed to improve various conditions related to brain cells and functions including dementia and Alzheimer's disease. Glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease. Therefore, this study was conducted to confirm the traditional claims by detection of active compounds, namely curcumin, gallic acid, catechin, rosmarinic acid, and andrographolide in the raw materials of Honey-iQfood through HPLC analysis, molecular docking, and dynamic simulations. Two potential compounds, andrographolide, and rosmarinic acid, produced the best binding affinities following the molecular docking of the active compounds against the GSK-3β and CDK5 targets. Andrographolide binds with GSK-3β at -8.2 kcal/mol, whereas rosmarinic acid binds to CDK5 targets at -8.6 kcal/mol. Molecular dynamics was further carried out to confirm the docking results and clarify their dynamic properties such as RMSD, RMSF, rGyr, SASA, PSA, and binding free energy. CDK5-andrographolide complexes had the best MM-GBSA score (-83.63 kcal/mol) compared to other complexes, indicating the better interaction profile and stability of the complex. These findings warrant further research into andrographolide and rosmarinic acid as efficient inhibitors of tau protein hyperphosphorylation to verify their therapeutic potential in brain-related illnesses.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3429-3448"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139074232","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}

{"title":"Novel computational and drug design strategies for the inhibition of human T-cell leukemia virus 1-associated lymphoma by Astilbin derivatives.","authors":"Shopnil Akash, Sajjat Mahmood, Rashel Ahamed, Imren Bayıl, Rahul Dev Bairagi, Md Rezaul Islam, Md Eram Hosen, Gabriela de Lima Menezes, Khalid S Almaary, Hiba-Allah Nafidi, Mohammed Bourhia, Lahcen Ouahmane","doi":"10.1080/07391102.2023.2294376","DOIUrl":"10.1080/07391102.2023.2294376","url":null,"abstract":"<p><p>Human T-cell leukemia virus 1 (HTLV-1) associated lymphoma is a devastating malignancy triggered by HTLV-1 infections. We employeda comprehensive drug design and computational strategy in this work to explore the inhibitory activitiesof Astilbin derivatives against HTLV-1-associated lymphoma. We evaluated the stability, binding affinities, and various computational analysis of Astilbin derivatives against target proteins, such as HTLV-1 main protease and HTLV-1 capsid protein. The root mean square deviation (RMSD), root mean square fluctuation, radius of gyration, hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) were applied to characterize these protein-ligand interactions further. Ligand-03 and ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while ligand-05 displayed high binding affinity to HTLV-1 protease. MD simulation analysis revealed that ligand-03, bound to HTLV-1 capsid protein, demonstrated enhanced stability with lower RMSD values and fewer conformational changes, suggesting a promising binding orientation. Ligand-04, despite stable binding, exhibited increased structural deviations, making it less suitable. Ligand-05 demonstrated stable binding to HTLV-1 protease throughout the simulation period at 100 nanoseconds. Hydrogen bond analysis indicated that ligand-05 formed persistent hydrogen bonds with significantresidues, contributing to its stability. PCA highlighted ligand-03's more remarkable conformational changes, while DCCM showed ligand-05's distinct dynamics, indicating its different behavior in the complex. Furthermore, binding free energy calculations supported the favorable interactions of ligand-03 and ligand-04 with HTLV-1 capsid protein, while ligand-05 showed weaker interactions with HTLV-1 protease. Molecular electrostatic potential and frontier molecular orbital analyses provided insights into these compounds' charge distribution and stability. In conclusion, this research found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma. Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04 and Ligand-05, which showed the most attractive binding profile with the target protein. These results open up new opportunities for innovative drug development, and more experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"2746-2761"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138829948","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}

{"title":"Targeting CDK6 in hormone receptor-positive breast cancer: inhibitor discovery for precision oncology through dynamics study.","authors":"Zeenat Khatoon, Mohammad Khalid, Mohammed H Alqarni, Ahmed I Foudah, Sivakumar Annadurai, Shadma Wahab, Mohammad Ali Abdullah Almoyad","doi":"10.1080/07391102.2023.2294375","DOIUrl":"10.1080/07391102.2023.2294375","url":null,"abstract":"<p><p>CDK6 is a critical protein involved in the regulation of the cell cycle, playing an important role in the progression from the G1 to S phase. In breast cancer, dysregulation of this protein is involved in tumour development and progression, particularly in hormone receptor-positive (HR+) breast cancers. The upregulation of CDK6 have been observed in a subset of breast cancers, leading to uncontrolled progression of the cell cycle and increased proliferation of cells. The purpose of this abstract is to provide an outline of CDK6's role. In breast cancer and the therapeutic strategies targeting CDK6 using specific selected inhibitors. To discover viable therapeutic candidates after competitive inhibition of CDK6 with a small molecular drug complex, high throughput screening and docking studies were used. Further, we carried the compounds based on ADMET properties and prediction of activity spectra for substances analysis. Finally, two different compounds were selected to carry out MD simulations. CDK6-IMPHY002642 and CDK6-IMPHY005260 are the two compounds that were identified. Overall, our results suggest that the CDK6-IMPHY002642 and CDK6-IMPHY005260 complex was relatively stable during the simulation. The compounds that have been found can also be further examined as potential therapeutic possibilities. The combined findings suggest that CDK6, together with their genetic changes, can be investigated in therapeutic interventions for precision oncology, leveraging early diagnostics and target-driven therapy.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"2733-2745"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138829949","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}

{"title":"Exploring antibiofilm potential of some new imidazole analogs against <i>C. albicans:</i> synthesis, antifungal activity, molecular docking and molecular dynamics studies.","authors":"Shahebaaz K Pathan, Amruta Shelar, Satish Deshmukh, Firoz A Kalam Khan, Siddique Akber Ansari, Irfan Aamer Ansari, Rajesh B Patil, Rohidas Arote, Omprakash Bhusnure, Rajendra H Patil, Jaiprakash N Sangshetti","doi":"10.1080/07391102.2023.2296604","DOIUrl":"10.1080/07391102.2023.2296604","url":null,"abstract":"<p><p>A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against <i>Candida albicans</i> was evaluated <i>in vitro</i>. Two of the synthesized derivatives <b>5e (</b>IC₅₀= 25 µg/mL) and <b>5m</b> (IC₅₀= 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC₅₀ = 40 µg/mL) against <i>C. albicans</i>. Based on the <i>in vitro</i> results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using <i>in-silico</i> molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins-ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb's free energy landscape analysis suggested greater affinity of the compounds <b>5e</b> and <b>5m</b> toward Als4 protein.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3099-3115"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087032","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}

{"title":"Salp-J Colony Optimization-based advanced hybrid ensemble deep predictor with LSTM for protein structure prediction.","authors":"Swati Jadhav, Arati J Vyavahare, Manish Sharma","doi":"10.1080/07391102.2023.2294386","DOIUrl":"10.1080/07391102.2023.2294386","url":null,"abstract":"<p><p>Protein structure prediction (PSP) is a key concern in computational biology, which is considered a challenging task that is vital to determine the structure and the protein function since each protein possesses a definite shape, whereas the protein secondary structure prediction (PSSP) is the foundation for three-dimensional PSP. An Advanced hybrid ensemble deep predictor is utilized for predicting the structure of a protein using Long-Short Term Memory (LSTM), in which the performance of the predictor is improved for obtaining the features through the Salp-J Colony Optimization, which is developed by integrating the features of three optimizations the exploration behavior of Ulmaris, the immune system of virus colony and the teamwork of salp for solution update that helps to predict the accurate protein structure. The proposed method achieved the value of 99.1% accuracy, 99.5% sensitivity, 98.85% specificity, and 0.9% error at the 80% of training percentage 90 using CullPDB. Similarly, in Protein Net, the attained value of accuracy is 97.27%, sensitivity is 98.13%, specificity is 97%, and error is 2.7% concerning training percentage 90%.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"2901-2916"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039408","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}

{"title":"Exploring the hub genes and potential drugs involved in Fanconi anemia using microarray datasets and bioinformatics analysis.","authors":"Alaa R Hameed, Sama Fakhri Ali, Taghreed N Almanaa, Mohammad Abdullah Aljasir, Abdulmohsen M Alruwetei, Samira Sanami, Hassan Ayaz, Ijaz Ali, Faisal Ahmad, Sajjad Ahmad","doi":"10.1080/07391102.2023.2297008","DOIUrl":"10.1080/07391102.2023.2297008","url":null,"abstract":"<p><p>Fanconi anemia (FA) is a genetic disorder that occurs when certain genes responsible for repairing DNA replication and promoting homologous recombination fail to function properly. This leads to severe clinical symptoms and a wide range of cancer-related characteristics. Recent treatment approaches for FA involve hematopoietic stem cell transplantation (HSCT), which helps restore the population of stem cells. A survival study using p-values indicated that specific hub genes play a significant role in diagnosing and predicting the disease. To find potential medications that interact with the identified hub genes, researchers inferred drugs. Among hub genes, TP53 was found to be particularly promising through computational analysis. Further investigation focused on two drugs, Topiramate and Tocofersolan predicted based on drug bank database analysis. Molecular docking strategies were employed to assess the best binding pose of these drugs with TP53. Topiramate showed a binding affinity of -6.5 kcal/mol, while Tocofersolan showed -8.5 kcal/mol against the active residues within the binding pocket. Molecular dynamics (MD) simulations were conducted to observe the stability of each drug's interaction with the TP53 protein over time. Both drugs exhibited stable confirmation with only slight changes in the loop region of the TP53 protein during the simulation intervals. Results also shows that there was a high fluctuation observed during apo-sate simulation time intervals as compared to complex system. Hence, it is suggested that the exploration of structure-based drug design holds promising results to specific target. This could potentially lead to a breakthrough in future experimental approaches for FA treatment.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3297-3310"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040038","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}

{"title":"Unleashing the binding interaction of chrysin-Cu(II) complex with the biomacromolecular targets: further studies of cell cytotoxicity and radical scavenging properties.","authors":"Sharat Sarmah, Ibemhanbi Konthoujam, Vivek Prakash, Kripamoy Aguan, Atanu Singha Roy","doi":"10.1080/07391102.2023.2300122","DOIUrl":"10.1080/07391102.2023.2300122","url":null,"abstract":"<p><p>Flavonoids are significant dietary components and have ability to coordinate with metal ions to produce novel drug discovery leads that are superior to those of the parent flavonoids. Here, in this report, we have synthesized chrysin-Cu(II) complex (as per reported article) and characterized it further with different analytical techniques. The synthesized complex was evaluated for radical scavenging and cell cytotoxicity studies where it exhibited enhanced activity as compared to bare chrysin. The interaction studies of the complex with ct-DNA (<i>K</i>_b ⁓ 10⁵ M^-1), human serum albumin (HSA) and ovalbumin (<i>K</i>_b ⁓ 10⁴ M^-1) were evaluated using multi-spectroscopic and molecular docking studies. Groove binding mode with ct-DNA was observed as confirmed from competitive displacement studies, viscosity measurement, melting temperature estimation and docking analyses. The complex exhibited comparatively higher affinity towards ct-DNA which indicated it efficient transportation by the carrier proteins and controlled release in the target DNA.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3671-3687"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377691","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}

{"title":"Biological evaluations and computational studies of newly synthesized thymol-based Schiff bases as anticancer, antimicrobial and antioxidant agents.","authors":"Dicle Sahin, Remziye Aysun Kepekci, Burçin Türkmenoğlu, Senem Akkoc","doi":"10.1080/07391102.2023.2297813","DOIUrl":"10.1080/07391102.2023.2297813","url":null,"abstract":"<p><p>Three new thymol-based molecules were synthesized and evaluated as anticancer, antimicrobial and antioxidant agents. Liver, colon, lung and prostate cancer cell lines were utilized in cytotoxicity tests. The results demonstrated that synthesized molecules had a cytotoxic effect against the screened cell lines. One of the molecules (<b>4a</b>) was found to have a higher efficacy towards the colon cancer cell line (DLD-1) with an IC₅₀ value of 12.39 µM and the other (<b>4c</b>) towards the prostate cancer cell line (PC3) with an IC₅₀ value of 7.67 µM than the positive control drug cisplatin. To assess the antimicrobial activity of molecules (<b>4a-c</b>), Gram-positive bacteria, Gram-negative bacteria and yeast were subjected to agar disc diffusion and broth microdilution assays. The investigation of antioxidant potential was conducted using the DPPH radical scavenging activity assay. While all compounds displayed strong cytotoxic and antioxidant properties, they exhibited only moderate antimicrobial activity. Molecular docking studies were performed on epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR-2), focal adhesion kinase (FAK), B-Raf and phosphoinositide 3-kinase (PI3K). The binding energies and interactions obtained from the docking results of compounds (<b>4a-c</b>) supported the experimental results. Drug similarity rates and pharmacokinetic properties were analyzed with the absorption, distribution, metabolism and excretion (ADME) method. Geometric parameters such as chemical potential (µ), electrophilicity index (ω) and chemical softness (σ) of compounds (<b>4a-c</b>) were calculated using the 6-31*G basis set B3LYP method.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3375-3389"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040037","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}

{"title":"Combining QSAR techniques, molecular docking, and molecular dynamics simulations to explore anti-tumor inhibitors targeting Focal Adhesion Kinase.","authors":"Yuan Liu, Jian-Bo Tong, Peng Gao, Xuan-Lu Fan, Xue-Chun Xiao, Yi-Chaung Xing","doi":"10.1080/07391102.2023.2301055","DOIUrl":"10.1080/07391102.2023.2301055","url":null,"abstract":"<p><p>Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (<math><mrow><msup><mrow><mi>q</mi></mrow><mrow><mn>2</mn></mrow></msup></mrow></math>= 0.715, <math><mrow><msup><mrow><mi>r</mi></mrow><mrow><mn>2</mn></mrow></msup></mrow></math>= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (<math><mrow><msup><mrow><mi>q</mi></mrow><mrow><mn>2</mn></mrow></msup></mrow></math>= 0.707, <math><mrow><msup><mrow><mi>r</mi></mrow><mrow><mn>2</mn></mrow></msup></mrow></math>= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3749-3765"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087029","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}