Abstract:
:Triple-negative breast cancers (TNBCs) are one of the most aggressive and complex forms of cancers in women. TNBCs are commonly known for their complex heterogeneity and poor prognosis. The present work aimed to develop a predictive 2D and 3D quantitative structure-activity relationship (QSAR) models against metastatic TNBC cell line. The 2D-QSAR was based on multiple linear regression analysis and validated by Leave-One-Out (LOO) and external test set prediction approach. QSAR model presented regression coefficient values for training set (r2), LOO-based internal regression (q2) and external test set regression (pred_r2) which are 0.84, 0.82 and 0.75, respectively. Five properties, Epsilon4 (electronegativity), ChiV3cluster (valence molecular connectivity index), chi3chain (retention index for three-membered ring), TNN5 (nitrogen atoms separated through 5 bond distance) and nitrogen counts, were identified as important structural features responsible for anticancer activity of MDA-MB-231 inhibitors. Five novel derivatives of glycyrrhetinic acid (GA) named GA-1, GA-2, GA-3, GA-4 and GA-5 were semi-synthesised and screened through the QSAR model. Further, in vitro activities of the derivatives were analysed against human TNBC cell line, MDA-MB-231. The result showed that GA-1 exhibits improved cytotoxic activity to that of parent compound (GA). Further, atomic property field (APF)-based 3D-QSAR and scoring recognise C-30 carboxylic group of GA-1 as major influential factor for its anticancer activity. The significance of C-30 carboxylic group in GA derivatives was also confirmed by molecular docking study against cancer target glyoxalase-I. Finally, the oral bioavailability and toxicity of GA-1 were assessed by computational ADMET studies.Communicated by Ramaswamy H. Sarma.
journal_name
J Biomol Struct Dynjournal_title
Journal of biomolecular structure & dynamicsauthors
Shukla A,Tyagi R,Meena S,Datta D,Srivastava SK,Khan Fdoi
10.1080/07391102.2019.1570868subject
Has Abstractpub_date
2020-01-01 00:00:00pages
168-185issue
1eissn
0739-1102issn
1538-0254journal_volume
38pub_type
杂志文章abstract::Communicated by Ramaswamy H. Sarma. ...
journal_title:Journal of biomolecular structure & dynamics
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