In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer.
| Title: | In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer. |
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| Authors: | Kalirajan R; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, A Constituent College of JSS Academy of Higher Education & Research-(Deemed to be University), Udhagamandalam - 643001 (Tamilnadu), India.; Pandiselvi A; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, A Constituent College of JSS Academy of Higher Education & Research-(Deemed to be University), Udhagamandalam - 643001 (Tamilnadu), India.; Gowramma B; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, A Constituent College of JSS Academy of Higher Education & Research-(Deemed to be University), Udhagamandalam - 643001 (Tamilnadu), India.; Balachandran P; Department of Pharmacy, Annamalai University, Chidambaram, (Tamilnadu), India. |
| Source: | Current drug research reviews [Curr Drug Res Rev] 2019; Vol. 11 (2), pp. 118-128. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Bentham Science Publishers Country of Publication: United Arab Emirates NLM ID: 101735701 Publication Model: Print Cited Medium: Internet ISSN: 2589-9783 (Electronic) Linking ISSN: 25899775 NLM ISO Abbreviation: Curr Drug Res Rev Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Saif Zone Sharjah, U.A.E] : Bentham Science Publishers, [2019]- |
| MeSH Terms: | Amsacrine/*analogs & derivatives ; Antineoplastic Agents/*pharmacology ; Breast Neoplasms/*drug therapy ; Isoxazoles/*pharmacology ; Erb-b2 Receptor Tyrosine Kinases/*antagonists & inhibitors; Amsacrine/chemistry ; Amsacrine/pharmacokinetics ; Amsacrine/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Ethacridine/pharmacology ; Isoxazoles/chemistry ; Isoxazoles/pharmacokinetics ; Tamoxifen/pharmacology ; Computer Simulation ; Drug Design ; Female ; Humans ; Hydrogen Bonding ; Models, Molecular ; Molecular Dynamics Simulation ; Structure-Activity Relationship |
| Abstract: | Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties.; Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2.; Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score.; Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive.; Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.; (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) |
| Contributed Indexing: | Keywords: Acridine; HER2; MM-GBSA; docking studies; in-silico ADMET screening; isoxazole. |
| Substance Nomenclature: | 00DPD30SOY (Amsacrine); 0 (Antineoplastic Agents); WIX85M1A6R (Ethacridine); 0 (Isoxazoles); EC 2.7.10.1 (Erb-b2 Receptor Tyrosine Kinases); 094ZI81Y45 (Tamoxifen); 3340-22-5 (9-anilinoacridine); EC 2.7.10.1 (ERBB2 protein, human) |
| Entry Date(s): | Date Created: 20190913 Date Completed: 20200520 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| DOI: | 10.2174/2589977511666190912154817 |
| PMID: | 31513003 |
| Database: | MEDLINE |
Journal Article