title: QSAR modeling of aromatase inhibitory activity of 1-substituted 1,2,3-triazole analogs of letrozole.
abstract: Aromatase is an estrogen biosynthesis enzyme belonging to the cytochrome P450 family that catalyzes the rate-limiting step of converting androgens to estrogens. As it is pertinent toward tumor cell growth promotion, aromatase is a lucrative therapeutic target for breast cancer. In the pursuit of robust aromatase inhibitors, a set of fifty-four 1-substituted mono- and bis-benzonitrile or phenyl analogs of 1,2,3-triazole letrozole were employed in quantitative structure-activity relationship (QSAR) study using multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM). Such QSAR models were developed using a set of descriptors providing coverage of the general characteristics of a molecule encompassing molecular size, flexibility, polarity, solubility, charge and electronic properties. Important physicochemical properties giving rise to good aromatase inhibition were obtained by means of exploring its chemical space as a function of the calculated molecular descriptors. The optimal subset of 3 descriptors (i.e. number of rings, ALogP and HOMO-LUMO) was further used for QSAR model construction. The predicted pIC₅₀ values were in strong correlation with their experimental values displaying correlation coefficient values in the range of 0.72-0.83 for the cross-validated set (QCV) while the external test set (Q(Ext)) afforded values in the range of 0.65-0.66. Insights gained from the present study are anticipated to provide pertinent information contributing to the origins of aromatase inhibitory activity and therefore aid in our on-going quest for aromatase inhibitors with robust properties.
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand. Electronic address: chanin.nan@mahidol.ac.th.
authors.forename: Chanin
authors.initials: C
authors.lastname: Nantasenamat
authors.forename: Apilak
authors.initials: A
authors.lastname: Worachartcheewan
authors.forename: Supaluk
authors.initials: S
authors.lastname: Prachayasittikul
authors.forename: Chartchalerm
authors.initials: C
authors.lastname: Isarankura-Na-Ayudhya
authors.forename: Virapong
authors.initials: V
authors.lastname: Prachayasittikul
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077289:Letrozole; D016014:Linear Models; D008958:Models, Molecular; D015394:Molecular Structure; D016571:Neural Networks, Computer; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase
keywords: Aromatase; Breast cancer; Chemical space; Letrozole; QSAR; Structure–activity relationship; Triazole