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2D- and 3D-QSAR modelling, molecular docking and in vitro evaluation studies on 18β-glycyrrhetinic acid derivatives against triple-negative breast cancer cell line

Shukla, Aparna ; Tyagi, Rekha ; Meena, Sanjeev ; Datta, Dipak ; Srivastava, Santosh Kumar ; Khan, Feroz

Journal of biomolecular structure & dynamics, 2020-01, Vol.38 (1), p.168-185 [Periódico revisado por pares]

England: Taylor & Francis

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Título:
2D- and 3D-QSAR modelling, molecular docking and in vitro evaluation studies on 18β-glycyrrhetinic acid derivatives against triple-negative breast cancer cell line
Autor: Shukla, Aparna ; Tyagi, Rekha ; Meena, Sanjeev ; Datta, Dipak ; Srivastava, Santosh Kumar ; Khan, Feroz
Assuntos: Algorithms ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; breast cancer ; Cell Line, Tumor ; glycyrrhetinic acid ; Glycyrrhetinic Acid - analogs & derivatives ; Glycyrrhetinic Acid - chemistry ; Glycyrrhetinic Acid - pharmacology ; glyoxalase-I ; Humans ; Hydrolysis ; MDA-MB-231 ; Models, Molecular ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; QSAR ; Quantitative Structure-Activity Relationship ; Triple Negative Breast Neoplasms ; triple-negative breast cancer
É parte de: Journal of biomolecular structure & dynamics, 2020-01, Vol.38 (1), p.168-185
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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 (r 2 ), LOO-based internal regression (q 2 ) and external test set regression (pred_r 2 ) 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
Editor: England: Taylor & Francis
Idioma: Inglês

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2D- and 3D-QSAR modelling, molecular docking and in vitro evaluation studies on 18β-glycyrrhetinic acid derivatives against triple-negative breast cancer cell line

Shukla, Aparna ; Tyagi, Rekha ; Meena, Sanjeev ; Datta, Dipak ; Srivastava, Santosh Kumar ; Khan, Feroz

England: Taylor & Francis

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