Tags

Type your tag names separated by a space and hit enter

Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling.
Chem Biol Interact. 2016 Apr 25; 250:12-26.CB

Abstract

Bcl-2 is an anti-apoptotic protein involved in cancer resistance to cytotoxic therapies making it an interesting target for inhibitors design. Towards this end, we implemented an elaborated ligand-based computational workflow that combines exhaustive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural features required for potent Bcl-2 inhibitors employing 98 known Bcl-2 inhibitors. Genetic function algorithm (GFA) coupled with k nearest neighbor (kNN) or multiple linear regression (MLR) analyses were employed to generate predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. The optimal QSAR-selected pharmacophore models were validated by receiver operating characteristic (ROC) curve analysis and by comparison with crystallographic structures of known inhibitors co-crystallized within Bcl-2 binding pocket. Optimal QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of new selective cytotoxic compounds against Bcl-2 expressing cancer cells. The hits were retrieved from the National Cancer Institute (NCI) structural database. Several potent hits were captured. The most potent hits illustrated IC50 values of 4.2 and 2.60 μM against MDA-MB-231 cancer cell-line.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Aboalhaija NH
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Zarqa University, Az-zarqa, Jordan.
Zihlif MA
Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan.
Taha MO
Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan. Electronic address: mutasem@ju.edu.jo.

MeSH

AlgorithmsAntineoplastic AgentsCell Line, TumorDrug DiscoveryHumansLigandsLinear ModelsModels, MolecularNeoplasmsProto-Oncogene Proteins c-bcl-2Quantitative Structure-Activity RelationshipSmall Molecule Libraries

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26954606

Citation

Aboalhaija, Nour H., et al. "Discovery of New Selective Cytotoxic Agents Against Bcl-2 Expressing Cancer Cells Using Ligand-based Modeling." Chemico-biological Interactions, vol. 250, 2016, pp. 12-26.
Aboalhaija NH, Zihlif MA, Taha MO. Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling. Chem Biol Interact. 2016;250:12-26.
Aboalhaija, N. H., Zihlif, M. A., & Taha, M. O. (2016). Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling. Chemico-biological Interactions, 250, 12-26. https://doi.org/10.1016/j.cbi.2016.03.006
Aboalhaija NH, Zihlif MA, Taha MO. Discovery of New Selective Cytotoxic Agents Against Bcl-2 Expressing Cancer Cells Using Ligand-based Modeling. Chem Biol Interact. 2016 Apr 25;250:12-26. PubMed PMID: 26954606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling. AU - Aboalhaija,Nour H, AU - Zihlif,Malek A, AU - Taha,Mutasem O, Y1 - 2016/03/05/ PY - 2015/10/08/received PY - 2016/02/28/revised PY - 2016/03/02/accepted PY - 2016/3/9/entrez PY - 2016/3/10/pubmed PY - 2016/8/18/medline KW - Anticancer screening KW - Bcl-2 KW - MLR KW - Pharmacophore KW - QSAR KW - Virtual screening KW - kNN SP - 12 EP - 26 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 250 N2 - Bcl-2 is an anti-apoptotic protein involved in cancer resistance to cytotoxic therapies making it an interesting target for inhibitors design. Towards this end, we implemented an elaborated ligand-based computational workflow that combines exhaustive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural features required for potent Bcl-2 inhibitors employing 98 known Bcl-2 inhibitors. Genetic function algorithm (GFA) coupled with k nearest neighbor (kNN) or multiple linear regression (MLR) analyses were employed to generate predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. The optimal QSAR-selected pharmacophore models were validated by receiver operating characteristic (ROC) curve analysis and by comparison with crystallographic structures of known inhibitors co-crystallized within Bcl-2 binding pocket. Optimal QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of new selective cytotoxic compounds against Bcl-2 expressing cancer cells. The hits were retrieved from the National Cancer Institute (NCI) structural database. Several potent hits were captured. The most potent hits illustrated IC50 values of 4.2 and 2.60 μM against MDA-MB-231 cancer cell-line. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/26954606/Discovery_of_new_selective_cytotoxic_agents_against_Bcl_2_expressing_cancer_cells_using_ligand_based_modeling_ DB - PRIME DP - Unbound Medicine ER -