Fei Xing, Zhicheng Wang, Noor Bahadar, Can Wang, Xu-Dong Wang
{"title":"山奈酚衍生物作为结肠癌 CDK2 潜在抑制剂的分子见解:药效学建模、对接和动态分析。","authors":"Fei Xing, Zhicheng Wang, Noor Bahadar, Can Wang, Xu-Dong Wang","doi":"10.3389/fchem.2024.1440196","DOIUrl":null,"url":null,"abstract":"<p><p>Cyclin-dependent kinase 2 (CDK2) has been recognized as one of the crucial factors in cell cycle regulation and has been proposed as a potential target for cancer therapies, particularly for colorectal cancer (CRC). Due to the increased incidence rate of CRC and challenges associated with existing treatment options, there is a need for efficient and selective anti-cancer compounds. The current work aims to explore the ability of novel kaempferol derivatives as CDK2 inhibitors by performing conceptual pharmacophore modeling, molecular docking, and molecular dynamic analysis. Kaempferol and its derivatives were obtained from PubChem, and the optimized 3D structures of the compounds were generated using Maestro Ligprep. Subsequently, a pharmacophore model was developed to identify compounds with high fitness values, resulting in the selection of several kaempferol derivatives for further study. We evaluated the ADMET properties of these compounds to assess their therapeutic potential. Molecular docking was conducted using Maestro and BIOVIA Discovery Studio version 4.0 to predict the binding affinities of the compounds to CDK2. The top candidates were subjected to MM-GBSA analysis to predict their binding free energies. Molecular dynamics simulations using GROMACS were performed to assess the thermodynamic stability of the ligand-protein complexes. The results revealed several kaempferol derivatives with high predicted binding affinities to CDK2 and favorable ADMET properties. Specifically, compounds <b>5281642, 5318980,</b> and <b>14427423</b> demonstrated binding free energies of -30.26, -38.66, and -34.2 kcal/mol, respectively. Molecular dynamics simulations indicated that these ligand-protein complexes remained stable throughout the simulation period, with RMSD values remaining below 2 Å. In conclusion, the identified kaempferol derivatives show potential as CDK2 inhibitors based on computational predictions and demonstrate stability in molecular dynamics simulations, suggesting their future application in CRC treatment by targeting CDK2. These computational findings encourage further experimental validation and development of kaempferol derivatives as anti-cancer agents.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371583/pdf/","citationCount":"0","resultStr":"{\"title\":\"Molecular insights into kaempferol derivatives as potential inhibitors for CDK2 in colon cancer: pharmacophore modeling, docking, and dynamic analysis.\",\"authors\":\"Fei Xing, Zhicheng Wang, Noor Bahadar, Can Wang, Xu-Dong Wang\",\"doi\":\"10.3389/fchem.2024.1440196\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cyclin-dependent kinase 2 (CDK2) has been recognized as one of the crucial factors in cell cycle regulation and has been proposed as a potential target for cancer therapies, particularly for colorectal cancer (CRC). Due to the increased incidence rate of CRC and challenges associated with existing treatment options, there is a need for efficient and selective anti-cancer compounds. The current work aims to explore the ability of novel kaempferol derivatives as CDK2 inhibitors by performing conceptual pharmacophore modeling, molecular docking, and molecular dynamic analysis. Kaempferol and its derivatives were obtained from PubChem, and the optimized 3D structures of the compounds were generated using Maestro Ligprep. Subsequently, a pharmacophore model was developed to identify compounds with high fitness values, resulting in the selection of several kaempferol derivatives for further study. We evaluated the ADMET properties of these compounds to assess their therapeutic potential. Molecular docking was conducted using Maestro and BIOVIA Discovery Studio version 4.0 to predict the binding affinities of the compounds to CDK2. The top candidates were subjected to MM-GBSA analysis to predict their binding free energies. Molecular dynamics simulations using GROMACS were performed to assess the thermodynamic stability of the ligand-protein complexes. The results revealed several kaempferol derivatives with high predicted binding affinities to CDK2 and favorable ADMET properties. Specifically, compounds <b>5281642, 5318980,</b> and <b>14427423</b> demonstrated binding free energies of -30.26, -38.66, and -34.2 kcal/mol, respectively. Molecular dynamics simulations indicated that these ligand-protein complexes remained stable throughout the simulation period, with RMSD values remaining below 2 Å. In conclusion, the identified kaempferol derivatives show potential as CDK2 inhibitors based on computational predictions and demonstrate stability in molecular dynamics simulations, suggesting their future application in CRC treatment by targeting CDK2. 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Molecular insights into kaempferol derivatives as potential inhibitors for CDK2 in colon cancer: pharmacophore modeling, docking, and dynamic analysis.
Cyclin-dependent kinase 2 (CDK2) has been recognized as one of the crucial factors in cell cycle regulation and has been proposed as a potential target for cancer therapies, particularly for colorectal cancer (CRC). Due to the increased incidence rate of CRC and challenges associated with existing treatment options, there is a need for efficient and selective anti-cancer compounds. The current work aims to explore the ability of novel kaempferol derivatives as CDK2 inhibitors by performing conceptual pharmacophore modeling, molecular docking, and molecular dynamic analysis. Kaempferol and its derivatives were obtained from PubChem, and the optimized 3D structures of the compounds were generated using Maestro Ligprep. Subsequently, a pharmacophore model was developed to identify compounds with high fitness values, resulting in the selection of several kaempferol derivatives for further study. We evaluated the ADMET properties of these compounds to assess their therapeutic potential. Molecular docking was conducted using Maestro and BIOVIA Discovery Studio version 4.0 to predict the binding affinities of the compounds to CDK2. The top candidates were subjected to MM-GBSA analysis to predict their binding free energies. Molecular dynamics simulations using GROMACS were performed to assess the thermodynamic stability of the ligand-protein complexes. The results revealed several kaempferol derivatives with high predicted binding affinities to CDK2 and favorable ADMET properties. Specifically, compounds 5281642, 5318980, and 14427423 demonstrated binding free energies of -30.26, -38.66, and -34.2 kcal/mol, respectively. Molecular dynamics simulations indicated that these ligand-protein complexes remained stable throughout the simulation period, with RMSD values remaining below 2 Å. In conclusion, the identified kaempferol derivatives show potential as CDK2 inhibitors based on computational predictions and demonstrate stability in molecular dynamics simulations, suggesting their future application in CRC treatment by targeting CDK2. These computational findings encourage further experimental validation and development of kaempferol derivatives as anti-cancer agents.
期刊介绍:
Frontiers in Chemistry is a high visiblity and quality journal, publishing rigorously peer-reviewed research across the chemical sciences. Field Chief Editor Steve Suib at the University of Connecticut is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to academics, industry leaders and the public worldwide.
Chemistry is a branch of science that is linked to all other main fields of research. The omnipresence of Chemistry is apparent in our everyday lives from the electronic devices that we all use to communicate, to foods we eat, to our health and well-being, to the different forms of energy that we use. While there are many subtopics and specialties of Chemistry, the fundamental link in all these areas is how atoms, ions, and molecules come together and come apart in what some have come to call the “dance of life”.
All specialty sections of Frontiers in Chemistry are open-access with the goal of publishing outstanding research publications, review articles, commentaries, and ideas about various aspects of Chemistry. The past forms of publication often have specific subdisciplines, most commonly of analytical, inorganic, organic and physical chemistries, but these days those lines and boxes are quite blurry and the silos of those disciplines appear to be eroding. Chemistry is important to both fundamental and applied areas of research and manufacturing, and indeed the outlines of academic versus industrial research are also often artificial. Collaborative research across all specialty areas of Chemistry is highly encouraged and supported as we move forward. These are exciting times and the field of Chemistry is an important and significant contributor to our collective knowledge.