Ligand- and Structure-Based Drug Design of Non-Steroidal Aromatase Inhibitors (NSAIs) in Breast Cancer

Ligand- and Structure-Based Drug Design of Non-Steroidal Aromatase Inhibitors (NSAIs) in Breast Cancer

Tarun Jha, Nilanajn Adhikari, Amit Kumar Halder, Achintya Saha
DOI: 10.4018/978-1-4666-8136-1.ch011
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Aromatase is a multienzyme complex overexpressed in breast cancer and responsible for estrogen production. It is the potential target for designing anti-breast cancer drugs. Ligand and Structure-Based Drug Designing approaches (LBDD and SBDD) are involved in development of active and more specific Nonsteroidal Aromatase Inhibitors (NSAIs). Different LBDD and SBDD approaches are presented here to understand their utility in designing novel NSAIs. It is observed that molecules should possess a five or six membered heterocyclic nitrogen containing ring to coordinate with heme portion of aromatase for inhibition. Moreover, one or two hydrogen bond acceptor features, hydrophobicity, and steric factors may play crucial roles for anti-aromatase activity. Electrostatic, van der Waals, and p-p interactions are other important factors that determine binding affinity of inhibitors. HQSAR, LDA-QSAR, GQSAR, CoMFA, and CoMSIA approaches, pharmacophore mapping followed by virtual screening, docking, and dynamic simulation may be effective approaches for designing new potent anti-aromatase molecules.
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Breast cancer, one of the commonest form (accounting for 35% of all cancers) among different types of life threatening malignancies in females, is responsible for 20% of all cancer deaths (Bandi, 2010). More than 5,22,000 women across the world died as a result of breast cancer (May, 2014). The maximum incidence of breast cancer is observed in the Western Europe, North America, Australia and New Zealand. The incidence of breast cancer is seven fold higher in developing nations. Belgium has the age-standardized highest rate of incidence (more than 110 cases per 1,00,000 women per annum). Apart from that, among top 12 countries, nine belong to Western European, but the Bahamas, Barbados and the United States of America are also in the top ranking. The 12 lowest incidence countries belong to mainly sub-Saharan Africa, South Asia and the far East, those suffer from poverty (May, 2014). The distribution pattern of the age-standardized mortality rate is different across the world. Belgium has the highest mortality followed by the Republic of Ireland with the highest rate of diagnosis but they are outranked by Fiji, Bahamas, Nigeria and Pakistan. Though the mortality is relatively low in low-incidence countries but the mortality rate and probability are higher than the high-incidence countries due to social and cultural influence, stage of presentation and the standards of health care. Due to the high incidence rate, breast cancer ranks top among women’s health concerns. Despite the advancement of new preventive strategies against breast cancer consideration, the incidence of breast cancer has remained the same since 2005 (Arumugam et al., 2014; Siegel et al., 2012). Breast carcinoma is most frequently diagnosed cancer in women apart from cancer of skin. Approximately 70% of the breast cancers are diagnosed in postmenopausal women (Howlader et al., 2014). It ranks second in tumor-related deaths after lung cancer (Muftuoglu & Mustata, 2010). It is predicted that one in eight American women is susceptible to develop invasive breast cancer in their lifetime (American Cancer Society Cancer Facts & Figures, 2013; Brueggemeier, Hackett, & Diaz-Cruz, 2005).

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