{"title":"3-deazaadenosine: A promising novel p38γ antagonist with potential as a breast cancer therapeutic agent","authors":"Pradeep Natarajan , Munikumar Manne , Swetha Kumari Koduru , Teja Sree Bokkasam","doi":"10.1016/j.ctarc.2023.100744","DOIUrl":null,"url":null,"abstract":"<div><p>Human p38γ protein kinase, or MAPK12, is a crucial signaling protein that is important in channelizing membrane signals to the nucleus in the MAPK cascade pathway, associated with breast and colorectal cancer, besides other forms of malignancies and atherosclerotic lesions too. P38γ has a significant contribution to the progression of breast carcinoma due to its multifaceted functions. Targeting p38γ for defining potent antagonists against p38γ can turn out to be an attractive and novel means of breast cancer therapeutics. Novel and potent lead molecules were designed utilizing computational drug design methodologies. Using high-throughput virtual screening, 1909 geometrically similar analogs of known inhibitors were generated, primarily using BIRB796, SB202190, ANP, CHEBI: 620708, and CHEBI: 524699. Chemical correctness was ensured using LigPrep for the standalone library, and Prep Wizard for p38γ using Maestro v.11.5. Using the Glide v5.5 flexible docking procedure on a standalone library of p38γ binding sites, we defined 18 potential leads and assessed their ADMET properties. Lead \"1\", among the proposed four p38γ antagonists with high-scoring and favorable interactions, was considered for 100 ns molecular dynamics simulations. Among the four proposed leads, Lead '1′ displayed consistent and stable bonding interactions with p38γ throughout the 100 ns molecular dynamics (MD) simulations. Additionally, it formed water bridges, contributing to its strong association with the protein. Notably, Lead '1′ (3-deazaadenosine) exhibited favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) within the acceptable range of pharmacological properties. Thus, 3-deazaadenosine and its mimetic might be promising new directions for developing a novel class of antagonists for breast cancer treatment.</p></div>","PeriodicalId":9507,"journal":{"name":"Cancer treatment and research communications","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer treatment and research communications","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2468294223000667","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
Human p38γ protein kinase, or MAPK12, is a crucial signaling protein that is important in channelizing membrane signals to the nucleus in the MAPK cascade pathway, associated with breast and colorectal cancer, besides other forms of malignancies and atherosclerotic lesions too. P38γ has a significant contribution to the progression of breast carcinoma due to its multifaceted functions. Targeting p38γ for defining potent antagonists against p38γ can turn out to be an attractive and novel means of breast cancer therapeutics. Novel and potent lead molecules were designed utilizing computational drug design methodologies. Using high-throughput virtual screening, 1909 geometrically similar analogs of known inhibitors were generated, primarily using BIRB796, SB202190, ANP, CHEBI: 620708, and CHEBI: 524699. Chemical correctness was ensured using LigPrep for the standalone library, and Prep Wizard for p38γ using Maestro v.11.5. Using the Glide v5.5 flexible docking procedure on a standalone library of p38γ binding sites, we defined 18 potential leads and assessed their ADMET properties. Lead "1", among the proposed four p38γ antagonists with high-scoring and favorable interactions, was considered for 100 ns molecular dynamics simulations. Among the four proposed leads, Lead '1′ displayed consistent and stable bonding interactions with p38γ throughout the 100 ns molecular dynamics (MD) simulations. Additionally, it formed water bridges, contributing to its strong association with the protein. Notably, Lead '1′ (3-deazaadenosine) exhibited favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) within the acceptable range of pharmacological properties. Thus, 3-deazaadenosine and its mimetic might be promising new directions for developing a novel class of antagonists for breast cancer treatment.
期刊介绍:
Cancer Treatment and Research Communications is an international peer-reviewed publication dedicated to providing comprehensive basic, translational, and clinical oncology research. The journal is devoted to articles on detection, diagnosis, prevention, policy, and treatment of cancer and provides a global forum for the nurturing and development of future generations of oncology scientists. Cancer Treatment and Research Communications publishes comprehensive reviews and original studies describing various aspects of basic through clinical research of all tumor types. The journal also accepts clinical studies in oncology, with an emphasis on prospective early phase clinical trials. Specific areas of interest include basic, translational, and clinical research and mechanistic approaches; cancer biology; molecular carcinogenesis; genetics and genomics; stem cell and developmental biology; immunology; molecular and cellular oncology; systems biology; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; cancer policy; and integration of various approaches. Our mission is to be the premier source of relevant information through promoting excellence in research and facilitating the timely translation of that science to health care and clinical practice.