Journal of Biomolecular Structure & Dynamics最新文献_第3页

Flavonoids as potential reactivators of structural mutation p53Y220C by computational and cell-based studies. 通过计算和细胞研究黄酮类化合物作为p53Y220C结构突变的潜在再激活剂。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-08-29 DOI: 10.1080/07391102.2023.2252071

Lakshay Malhotra, Punit Kaur, Abdul Samath Ethayathulla

{"title":"Flavonoids as potential reactivators of structural mutation p53Y220C by computational and cell-based studies.","authors":"Lakshay Malhotra, Punit Kaur, Abdul Samath Ethayathulla","doi":"10.1080/07391102.2023.2252071","DOIUrl":"10.1080/07391102.2023.2252071","url":null,"abstract":"The p53 Y220C is one of the most frequently observed structural mutants in various human cancers. The substitution of residue Tyr to Cys makes the p53 DNA binding domain susceptible to solvent entry into the hydrophobic core of the domain thereby destabilizing p53, which results in loss of its tumor suppressor activity. The mutation creates a structural crevice at the region between S3/S4 and S7/S8 loops in the DNA binding domain which can be targeted by small molecules. Studies have shown that the synthetic and natural compounds could bind to this crevice and restore the structure and function of the mutant p53Y220C to the wild type. In our previous study, we have shown Curcumin could rescue the function of mutant p53Y220C in pancreatic cancer cell line BxPC-3 harboring genomic mutation. In this study, we explored six flavonoids structurally similar to Curcumin such as Apigenin, Isoliquiritigenin, Liquiritigenin, Luteolin, Methylophiopogonanone A (MPA), and Methylophiopogonanone B (MPB) to test their potency to restore p53Y220C by molecular docking, molecular dynamics simulations and cytotoxicity assay. The secondary structure analysis after the MD simulations suggested that these compounds could stabilize the mutant p53 DNA binding domain to the wild type. In the cell-based cytotoxicity studies using p53Y220C harbouring BxPC-3 cell lines, the compounds MPA and MPB showed 75% cell death at 100 µM concentration. We proposed that the flavonoids MPA and MPB have the therapeutic potential to restore p53Y220C and could be used as a combinatorial therapy to reduce the dosage burden.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From sleep to cancer to neurodegenerative disease: the crucial role of Hsp70 in maintaining cellular homeostasis and potential therapeutic implications. 从睡眠到癌症再到神经退行性疾病:热休克蛋白70在维持细胞稳态中的关键作用及其潜在的治疗意义

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-08-29 DOI: 10.1080/07391102.2023.2252509

Shampa Ghosh, Kshitij Vashisth, Soumya Ghosh, Sung Soo Han, Rakesh Bhaskar, Jitendra Kumar Sinha

{"title":"From sleep to cancer to neurodegenerative disease: the crucial role of Hsp70 in maintaining cellular homeostasis and potential therapeutic implications.","authors":"Shampa Ghosh, Kshitij Vashisth, Soumya Ghosh, Sung Soo Han, Rakesh Bhaskar, Jitendra Kumar Sinha","doi":"10.1080/07391102.2023.2252509","DOIUrl":"10.1080/07391102.2023.2252509","url":null,"abstract":"Sleep is a fundamental process essential for reparatory and restorative mechanisms in all organisms. Recent research has linked sleep to various pathological conditions, including cancer and neurodegeneration, which are associated with various molecular changes in different cellular environments. Despite the potential significance of various molecules, the HSPA1A or Hsp70 protein, which has possible connections with sleep and different neuropsychological and pathological disorders, has been explored the least. This paper explores the potential for manipulating and discovering drugs related to the Hsp70 protein to alleviate sleep problems and improve the prognosis for various other health issues. This paper discusses the critical role of Hsp70 in cancer, neurodegeneration, apoptosis, sleep, and its regulation at the structural level through allosteric mechanisms and different substrates. The significant impact of Hsp70's connection to various conditions suggests that existing sleep medicine could be used to improve such conditions, leading to improved outcomes, minimized research costs, and a new direction for current research. Overall, this paper highlights the potential of Hsp70 protein as a key therapeutic target for developing new drugs for the treatment of sleep disorders, cancer, neurodegeneration, and other related pathological conditions. Further research into the molecular mechanisms of Hsp70 regulation and its interactions with other cellular pathways is necessary to develop targeted treatments for these conditions.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10111974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Elucidating the material basis and potential mechanisms of Daqinglong Decoction acting on influenza by UPLC-Q-TOF/MS and network pharmacology. 利用UPLC-Q-TOF/MS和网络药理学研究大青龙汤治疗流行性感冒的物质基础和潜在机制。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-11-14 DOI: 10.1080/07391102.2023.2275173

Gong Xiao-Yan, Zhang Qiong-Yu, Tang Si-Yuan

{"title":"Elucidating the material basis and potential mechanisms of Daqinglong Decoction acting on influenza by UPLC-Q-TOF/MS and network pharmacology.","authors":"Gong Xiao-Yan, Zhang Qiong-Yu, Tang Si-Yuan","doi":"10.1080/07391102.2023.2275173","DOIUrl":"10.1080/07391102.2023.2275173","url":null,"abstract":"Daqinglong Decoction (DQLD), a traditional Chinese medicine (TCM) prescription firstly recorded in Shang han lun (the treatise on febrile diseases), has been used hundreds of years for the clinical treatment of influenza. However, the chemical composition and therapeutic mechanism of this prescription are unclear. UPLC-Q-TOF/MS was employed to analyze the chemical compounds in both methanol and boiling water extracts of DQLD. The compounds were then screened, characterized, and filtered using the TCMSP, TCMIP, TCM-ID and SymMap database, with a focus on their oral bioavailability and drug-likeness values. The resulting data were analyzed and optimized using the R language platform, Autodock and Gromacs software to identify biological processes and pathways. A total of 121 compounds were identified, of which 5 showed good binding ability to influenza virus targets (1L1B, IL10, CASP3, STAT3, TNF, and others). The active ingredient-target-influenza virus pathway was constructed using a network drug target analysis model prediction of DQLD, which was mainly enriched in Human cytomegalovirus infection, PI3K-Akt, HIF-1, and other signaling pathways through 1L1B, IL10 and other targets. Those pathways highly correlated to the body's inflammatory response, improve immunity, and exert anti-influenza virus effects. In summary, this study demonstrated that DQLD's active ingredients can effectively bind to influenza virus targets and exert anti-influenza virus effects by reducing inflammation and improving immunity through Human cytomegalovirus infection, PI3K-Akt and HIF-1 signaling pathways. These findings offer important insights into the potential mechanisms of action of DQLD and its potential use as a TCM against influenza and other viral infections.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92154450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Predicting the changes in neutralizing antibody interaction with G protein derived from Bangladesh isolates of Nipah virus: molecular dynamics based approach. 预测中和抗体与来自孟加拉国尼帕病毒分离株的G蛋白相互作用的变化:基于分子动力学的方法。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-08-29 DOI: 10.1080/07391102.2023.2252084

Norine Dsouza, Selvaa Kumar C

{"title":"Predicting the changes in neutralizing antibody interaction with G protein derived from Bangladesh isolates of Nipah virus: molecular dynamics based approach.","authors":"Norine Dsouza, Selvaa Kumar C","doi":"10.1080/07391102.2023.2252084","DOIUrl":"10.1080/07391102.2023.2252084","url":null,"abstract":"The infectious Nipah virus (NiV) is categorized into NiV-M (Malaysia) and NiV-B (Bangladesh) groups based on its genome comparison, pathogenicity, and mortality rate. The development of therapeutic molecules has used NiV-M-derived data in multiple studies than NiV-B. In continuation with this, the protein level investigation is also less explored to understand the interaction with therapeutic neutralizing antibodies for NiV-B. So, this study focuses on understanding the impact of NiV-B-specific mutations on the interaction of therapeutic neutralizing antibodies with the G protein. The population-based comparative analysis of NiV-B G protein sequences with NiV-M sequence identified twenty-six mutations. These predominantly polar mutations were then used to model the mutant protein (G_MT). In a comparative study, the G protein G_MT and reference protein G_WT (Malaysian origin) were subjected to a protein docking with neutralizing human monoclonal antibody HENV26. The binding affinity and the free binding energy of the glycoprotein in complex with G-WT and G_MT were calculated using PRODIGY and MM/PBSA tools respectively. Based on the PRODIGY report, G-WT showed stronger binding (-13.8 kcal/mol) compared to that of the G_MT (-9.0 kcal/mol) with the HENV26 antibody. The stability of the complexes was evaluated using MM/PBSA which showed higher binding energy with HENV26 for G_WT (-75.11 kcal/mol) in contrast to G_MT (-41.66 kcal/mol). The results indicate that the mutant G protein has a reduced ability to bind to neutralizing antibodies, resulting in a decreased effectiveness against strains carrying these mutations.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico identification of potential protein kinase C alpha inhibitors from phytochemicals from IMPPAT database for anticancer therapeutics: a virtual screening approach. 从IMPPAT数据库的植物化学物质中识别潜在的蛋白激酶C α抑制剂用于抗癌治疗:一种虚拟筛选方法。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-08-29 DOI: 10.1080/07391102.2023.2252086

Saad Ali Alshehri, Shadma Wahab, Mohammad Ali Abdullah Almoyad

{"title":"In silico identification of potential protein kinase C alpha inhibitors from phytochemicals from IMPPAT database for anticancer therapeutics: a virtual screening approach.","authors":"Saad Ali Alshehri, Shadma Wahab, Mohammad Ali Abdullah Almoyad","doi":"10.1080/07391102.2023.2252086","DOIUrl":"10.1080/07391102.2023.2252086","url":null,"abstract":"Protein Kinase C alpha (PKCα) is a critical signaling molecule that plays a crucial role in various physiological processes, including cell growth, differentiation, and survival. Over the years, there has been a growing interest in targeting PKCα as a promising drug target for the treatment of various diseases, including cancer. Targeting PKCα can, therefore, serve as a potential strategy to prevent cancer progression and enhance the efficacy of conventional anticancer therapies. We conducted a systematic search for promising compounds for their anticancer potential that target PKCα using natural compounds from the IMPPAT database. The initial compounds were screened through various tests, including analysis of their physical and chemical properties, PAINS filter, ADMET analysis, PASS analysis, and specific interaction analysis. We selected those that showed high binding affinity and specificity to PKCα from the screened compounds, and we further analyzed them using molecular dynamics simulations (MDS) and principal component analysis (PCA). Various systematic parameters from the MDS analyses suggested that the protein-ligand complexes were stabilized throughout the simulation trajectories of 100 nanoseconds (ns). Our findings indicated that compounds Nicandrenone and Withaphysalin D bind to PKCα with high stability and affinity, making them potential candidates for further research in cancer therapeutics innovation in clinical contexts.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computer-aided anti-cancer drug discovery of EGFR protein based on virtual screening of drug bank, ADMET, docking, DFT and molecular dynamic simulation studies. 基于药物库、ADMET、对接、DFT和分子动力学模拟研究的EGFR蛋白计算机辅助抗癌药物发现。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-09-07 DOI: 10.1080/07391102.2023.2252092

Miah Roney, Amit Dubey, Muhammad Hassan Nasir, Aisha Tufail, Saiful Nizam Tajuddin, Mohd Fadhlizil Fasihi Mohd Aluwi, Akm Moyeenul Huq

{"title":"Computer-aided anti-cancer drug discovery of EGFR protein based on virtual screening of drug bank, ADMET, docking, DFT and molecular dynamic simulation studies.","authors":"Miah Roney, Amit Dubey, Muhammad Hassan Nasir, Aisha Tufail, Saiful Nizam Tajuddin, Mohd Fadhlizil Fasihi Mohd Aluwi, Akm Moyeenul Huq","doi":"10.1080/07391102.2023.2252092","DOIUrl":"10.1080/07391102.2023.2252092","url":null,"abstract":"Numerous malignancies, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia, are brought on by aberrant tyrosine kinase signaling. Since the current chemotherapeutic medicines are toxic, there is a great need and demand from cancer patients to find novel chemicals that are toxic-free or have low toxicity and that can kill tumor cells and stop their growth. This work describes the in-silico examination of substances from the drug bank as EGFR inhibitors. Firstly, drug-bank was screened using the pharmacophore technique to select the ligands and Erlotinib (DB00530) was used as matrix compound. The selected ligands were screened using ADMET and the hit compounds were subjected to docking. The lead compound from the docking was subjected to DFT and MD simulation study. Using the pharmacophore technique, 23 compounds were found through virtual drug bank screening. One hit molecule from the ADMET prediction was the subject of docking study. According to the findings, DB03365 molecule fits to the EGFR active site by several hydrogen bonding interactions with amino acids. Furthermore, DFT analysis revealed high reactivity for DB03365 compound in the binding pocket of the target protein, based on ELUMO, EHOMO and band energy gap. Furthermore, MD simulations for 100 ns revealed that the ligand interactions with the residues of EGFR protein were part of the essential residues for structural stability and functionality. However, DB03365 was a promising lead molecule that outperformed the reference compound in terms of performance and in-vitro and in-vivo experiments needs to validate the study.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HPTLC based quantification of β-sitosterol from the leaves of Nyctanthes arbor-tristis and in-silico prediction of potential drug targeted towards cancer therapy. 基于HPTLC的β-谷甾醇含量测定和癌症治疗潜在靶向药物的计算机模拟预测。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-11-01 DOI: 10.1080/07391102.2023.2275171

Shruti Shree Pareek, Pratima Vijayvargia, Saroj Kumar Jha, Deepika Khandelwal, Rekha Vijayvergia

{"title":"HPTLC based quantification of β-sitosterol from the leaves of Nyctanthes arbor-tristis and in-silico prediction of potential drug targeted towards cancer therapy.","authors":"Shruti Shree Pareek, Pratima Vijayvargia, Saroj Kumar Jha, Deepika Khandelwal, Rekha Vijayvergia","doi":"10.1080/07391102.2023.2275171","DOIUrl":"10.1080/07391102.2023.2275171","url":null,"abstract":"Nyctanthes arbor-tristis (N. arbor-tristis) is a plant of enormous medicinal importance and each part of the plant retained extensive medicinal properties, such as antimicrobial, antioxidant, anticancer and anti-inflammatory activities, etc. Phytosterols are secondary metabolites of plants that are well-known for their ability to reduce cholesterol, boost immunity and inhibit the formation of cancer cells. In this study, β-sitosterol, which boosts antioxidant enzymes and reduces oxidative stress, was qualitatively and quantitatively identified in the methanolic extract of the plant's leaves using the HPTLC. Our findings show that N. arbor-tristis has a significant concentration of β-sitosterol with the 0.64 Rf value. Further, docking and simulation (in-silico) studies have shown that β-sitosterol has good binding affinity with human DNA Topoisomerase I (h-DNA Topo I) and has the potential to inhibit its activity. It can be reconstructed as h-DNA Topo I determent.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71423876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of coastal pesticide pollutants as potent inhibitors of Bacillus pasteurii urease mediated calcium carbonate precipitation: a computational approach. 鉴定沿海农药污染物作为巴氏杆菌脲酶介导的碳酸钙沉淀的有效抑制剂:一种计算方法。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-09-10 DOI: 10.1080/07391102.2023.2252089

Aparna Ganapathy Vilasam Sreekala, Krishna Kant Gupta, Vinod Kumar Nathan

{"title":"Identification of coastal pesticide pollutants as potent inhibitors of Bacillus pasteurii urease mediated calcium carbonate precipitation: a computational approach.","authors":"Aparna Ganapathy Vilasam Sreekala, Krishna Kant Gupta, Vinod Kumar Nathan","doi":"10.1080/07391102.2023.2252089","DOIUrl":"10.1080/07391102.2023.2252089","url":null,"abstract":"Microbially induced calcite precipitation (MICP) through urease enzyme has attained a lot of recognition in various fields of civil engineering and geotechnology for stabilizing the strength of soil and various concrete materials. The activity of urease has been found to be affected by various factors like temperature, substrate concentrations, pH of the medium, presence of inhibitors, etc. Through this study, the outcome of the interaction of pesticides (commonly found in Indian coastal regions) on Bacillus pasteurii urease, a major organism reported for MICP studies has been investigated in silico. The results from the study revealed that the enzyme has higher interactions of -4.1, -3.2, and -3.4 kJ/mol with common pesticides like dichloro diphenyl dichloro ethane(DDD), dichloro diphenyl trichloroe thane (DDT), and methyl parathion of organochlorides and organophosphates class. From the molecular dynamics simulation analysis, complex 1 (DDD -receptor) has been found to have the highest and more compact structure followed by methyl parathion -receptor. Prime MM-GBSA analysis also revealed the highest binding energy of -27.8 kcal/mol with the protein and DDD. Thus, it can be inferred from the current study that pesticides, particularly, DDD, DDT, and methyl parathion present in the coastal areas may have an impact on urease. This interaction can result in the inhibition of the urease activity of B. pasteurii, thus preventing the biomineralization process. This study would be the first report on the computational approach to understanding the interaction of prominent pesticides on the coastal region and B. pasteurii urease.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10193412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insilico molecular modelling to identify PDK-1 targeting agents based on its protein-protein docking interaction. 根据蛋白质与蛋白质之间的对接相互作用，通过内嵌分子建模确定 PDK-1 靶向药物。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-08-30 DOI: 10.1080/07391102.2023.2252080

Kailasam N Vennila, Kuppanagounder P Elango

{"title":"Insilico molecular modelling to identify PDK-1 targeting agents based on its protein-protein docking interaction.","authors":"Kailasam N Vennila, Kuppanagounder P Elango","doi":"10.1080/07391102.2023.2252080","DOIUrl":"10.1080/07391102.2023.2252080","url":null,"abstract":"PDK1, an attractive cancer target that downstreams 23 other kinases towards cell growth, survival and metabolism has gaining attention due to allosteric effect of ligands bound to it. Generally, the drug design strategy using pharmacophores is either a single protein structure or ensemble or ligand-based. Apart from these methods, yet another new approach of protein-protein docking with state of art computational tool like Schrodinger Suite to generate pharmacophores based on the interacting partners of the protein is proposed in this work. The structure-based pharmacophoric features were picked up from docking the ten interacting partners of PDK1 and screened against the Enamine libraries containing protein-protein interacting compound collection, advanced, protein mimetic and allosteric compounds. High throughput virtual screening against the PIF pocket of PDK1 yields an indole scaffold. The identified indole derivative is proposed to be a strong activator that binds in the protein-protein interaction site of PDK1 which was further confirmed by molecular metadynamics simulations, free energy surface analysis and MM-GBSA calculations. Thus, the pharmacophores generated by the interacting proteins for PPI can facilitate the virtual screening in structure-based drug discovery of similar therapeutic targets.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10468781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational Prediction of 3,5-Diaryl-1H-Pyrazole and spiropyrazolines derivatives as potential acetylcholinesterase inhibitors for alzheimer disease treatment by 3D-QSAR, molecular docking, molecular dynamics simulation, and ADME-Tox. 通过三维-QSAR、分子对接、分子动力学模拟和 ADME-Tox 计算预测 3,5-Diaryl-1H-Pyrazole 和 spiropyrazolines 衍生物作为治疗老年痴呆症的潜在乙酰胆碱酯酶抑制剂。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2024-11-01 Epub Date: 2023-09-01 DOI: 10.1080/07391102.2023.2252116

Moulay Ahfid El Alaouy, Marwa Alaqarbeh, Mohamed Ouabane, Hanane Zaki, Mohamed ElBouhi, Hassan Badaoui, Youness Moukhliss, Abdelouahid Sbai, Hamid Maghat, Tahar Lakhlifi, Mohammed Bouachrine

{"title":"Computational Prediction of 3,5-Diaryl-1H-Pyrazole and spiropyrazolines derivatives as potential acetylcholinesterase inhibitors for alzheimer disease treatment by 3D-QSAR, molecular docking, molecular dynamics simulation, and ADME-Tox.","authors":"Moulay Ahfid El Alaouy, Marwa Alaqarbeh, Mohamed Ouabane, Hanane Zaki, Mohamed ElBouhi, Hassan Badaoui, Youness Moukhliss, Abdelouahid Sbai, Hamid Maghat, Tahar Lakhlifi, Mohammed Bouachrine","doi":"10.1080/07391102.2023.2252116","DOIUrl":"10.1080/07391102.2023.2252116","url":null,"abstract":"The efficacy of 40 synthesized variants of 3,5-diaryl-1H-pyrazole and spiropyrazoline' derivatives as acetylcholinesterase inhibitors is verified using a quantitative three-dimensional structure-activity relationship (3D-QSAR) by comparative molecular field analysis (CoMFA) and molecular similarity index analysis (CoMSIA) models. In this research, different field models proved that CoMSIA/SE model is the best model with high predictive power compared to several models (Qved2 = O.65; R2 = 0.980; R2test = 0.727). Also, contour maps produced by CoMSIA/SE model have been employed to prove the key structural needs of the activity. Consequently, six new compounds have been generated. Among these compounds, M4 and M5 were the most active but remained toxic and had poor absorption capacities. While the M1, M2, M3 and M6 remained highly active while respecting ADMET's characteristics. Molecular docking results showed compound M2 better with acetylcholinesterase than compound 22. The interactions are classical hydrogen bonding with residues TYR:124, TYR:72, and SER:293, which play a critical role in the biological activity as AChE inhibitors. MD results confirmed the docking results and showed that compound M2 had satisfactory stability with (ΔGbinding = -151.225 KJ/mol) in the active site of AChE receptor compared with compound 22 (ΔGbinding = -133.375 KJ/mol). In addition, both compounds had good stability regarding RMSD, Rg, and RMSF. The previous results show that the newly designed compound M2 is more active in the active site of AChE receptor than compound 22.Communicated by Ramaswamy H. Sarma.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10129971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0