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KEY TERMS AND DEFINITIONS
AChE Enzyme: An enzyme that catalyses the hydrolysis of acetylcholine to acetate and choline.
Alzheimer’s Disease: It is a neurodegenerative disorder coined by German psychiatrist and neuro-
pathologist Alois Alzheimer in 1906.
GFA: Genetic function approximation is genetics based linear regression method of variable selection
that combines Holland’s genetic algorithm with Friedman’s multivariate adaptive regression splines.
In Silico: A Latin type expression and define the work performed using computer simulation or
computer modeling.
QSAR: Quantitative structure–activity relationship models are statistical regression equations used
in the chemical, biological and engineering sciences. Model influences the chemical structure, descriptor, physico-chemical properties on different physical, chemical and biological endpoints, as well as in
understanding the chemical processes.
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Chapter 11
Ligand- and Structure-
Based Drug Design of Non-
Steroidal Aromatase Inhibitors
(NSAIs) in Breast Cancer
Tarun Jha
Jadavpur University, India
Nilanajn Adhikari
Jadavpur University, India
ABSTRACT
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 π-π 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.
INTRODUCTION
Amit Kumar Halder
Jadavpur University, India
Achintya Saha
University of Calcutta, India
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
DOI: 10.4018/978-1-4666-8136-1.ch011
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Ligand- and Structure-Based Drug Design of NSAIs in Breast Cancer
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).
Sex hormones play crucial roles like growth regulation, maturation and reproduction in living
animals. Sex hormones are composed of a steroidal cyclopentanoperhydrophenanthrene nucleus.
Steroidal hormones are involved in regulation of different physiological effects, like muscle and hair
growth, fertility, water retention and dilatation of the capillary vessels as well as sebaceous gland
activity (Proteau, 2011; Davis et al., 2004; Morales et al., 2004). Estrogen is a prominent regulator
of cell proliferation in the tumorogenesis of hormone-dependent breast cancer and other tumors. The
exact mechanisms of this incidence are still hypothesized. Estrogen metabolites like reactive quinones
may directly interact with DNA. It causes mutations that are responsible for these proliferative effects
(Miller, 2003). Nearly, two-thirds of breast tumors are hormone-dependent and require estrogens to
grow (Brueggemeier, Hackett, & Diaz-Cruz, 2005; Howell, 2005; Muti, Rogan, & Cavalieri, 2006).
This phenomenon demands application of an endocrine therapy with a more favorable activity profile
and less adverse effects compared to unspecific chemotherapy. More than 100 years ago, Beatson
reported that ovariectomy in premenopausal women with breast cancer can induce tumor remission
(Beatson, 1896). By knowing the advantage of lowering estrogen level in breast cancer, antihormonal
therapy led to the development of new drug candidates. As high serum levels of estrogen is seen in
progression of breast cancer, two pharmacological strategies have been employed successfully to
control breast cancer (Murthy, Rao, & Sastry, 2004). Drugs either act through estrogen receptor (ER)
modulation (Ariazi et al., 2006) or interfere with the biosyntheses of steroidal hormones by inhibiting the enzyme controlling the interconversion from androgenic precursors, i.e., aromatase inhibitors
(AIs) (Brueggemeier, Hackett, & Diaz-Cruz, 2005). Considerable research work has been devoted to
the study of this aromatase enzyme. This helps to develop potent and selective agents that are able
to interfere with enzymatic action. Selective estrogen receptor modulators (SERMs) and aromatase
inhibitors (AIs) are successfully utilized as therapeutically important weapons in the battle against
breast cancer deaths (Pasqualini, 2004). Several classes of steroidal and nonsteroidal aromatase inhibitors are developed (Brodie, Sabnis, & Jelovac, 2006; Neves et al., 2009; Colozza et al., 2008; Dutta
& Pant, 2008; Eisen et al., 2008; Gobbi et al., 2008; Jackson et al., 2008; Osborne & Tripathy, 2005;
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Ligand- and Structure-Based Drug Design of NSAIs in Breast Cancer
Osborne & Schiff, 2005; Recanatini & Cavalli, 1998; Recanatini, Cavalli, & Valenti, 2002; Spinelli
et al., 2008). Steroidal aromatase inhibitors (Figure 1) like formaestane (1) and exemestane (2), and
nonsteroidal aromatase inhibitors, e.g., aminoglutethimide (3), fadrozole (4), anastrozole (5), letrozole
(6) and verozole (7) were evaluated successfully in clinical trials (Miller, 2003; Recanatini, Cavalli,
& Valenti, 2002).
Steroidal aromatase inhibitors (SAIs) are analogs of androgenic substrates. These inhibit aromatase
irreversibly by either competitive or mechanism-based way. Competitive inhibitors bind covalently
to the aromatase enzyme, whereas mechanism-based inhibitors, also called suicide inhibitors are
converted into a reactive intermediate which covalently binds with the enzyme and thereby permanently inactivates it. The enzyme is often destabilized by this process and the rate of degradation
by the intracellular proteosome is increased (Miller et al., 2008; Hong et al., 2007). On the other
Figure 1. Aromatase inhibitors (AIs) evaluated in clinical trials
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Ligand- and Structure-Based Drug Design of NSAIs in Breast Cancer
hand, nonsteroidal aromatase inhibitors (NSAIs) bind noncovalently to the aromatase enzyme. These
block the active site and reversibly inhibit the enzyme (Brueggemeier, Hackett, & Diaz-Cruz, 2005;
Hong et al., 2007). The NSAIs are divided according to the order of their discovery. Currently, 3
rd
generation of triazole derivatives is approved as front-line therapy for early and advanced cases of
breast cancer in postmenopausal women (Hong et al., 2007; Neves et al., 2009). However, as far as
the adverse effects are concerned in both steroidal and nonsteroidal AIs, these vary from mild to
severe and short term to long term. The SAIs produce androgenic side effects where different other
hormone-dependent physiological systems are disturbed due to lack of inhibitor specificity (Geisler
& Lonning, 2005). Prolonged estrogen deprivation may lead to osteoporosis and infertility as well
as other types of cancers (Hong et al., 2007). Hence, benefits of these SAIs may be suppressed
due to life-threatening adverse effects. Many patients are compelled to discontinue the use of this
type of inhibitors. Thus, more selective and less toxic aromatase inhibitors are needed. These are
required as the stability, efficiency and sensitivity to different classes of AIs may vary from patient
to patient due to mutations of intratumoral aromatase (Miller et al., 2008). The major advantage of
NSAIs is devoid of different steroidal adverse effects shown by steroidal AIs.
Drug design, development and discovery are expensive as well as time consuming processes.
Traditionally, drug discovery relies on synthesis and screening of large number of compounds to
identify a potential lead. Over the decades, there is an increased effort to apply computational approaches to combine both chemical and biological spaces in order to streamline drug design, optimization, discovery and development (Kapetanovic, 2008). Computational methods may play crucial
roles in understanding the specific molecular recognition events of the target macromolecule with
candidate hits (Shaikh et al., 2007). Rational drug design (RDD) methods may reduce time and cost
involved in drug development process in comparison to traditional drug discovery methods. The
RDD methods are utilized to design new inhibitors as well as for optimizing the pharmacokinetic
and toxicity profiles of lead molecules. The RDD approaches (Figure 2) can be categorized in two
types, i.e., ligand based drug design (LBDD) and structure based drug design (SBDD) (Aparoy,
Reddy, & Reddanna, 2012).
Though a limited number of molecular modeling studies for designing the SAIs (Numazawa,
Shelangouski, & Nagasaka, 2000; Beger et al., 2001; Numazawa et al., 2002; Polanski & Gieleciak,
2003; Murthy et al., 2006; Dai et al., 2010; Roy & Roy, 2010a) and NSAIs (Muftuoglu & Mustata,
2010; Recanatini & Cavalli, 1998; Furet et al., 1993; Nagy, Tokarski, & Hopfinger, 1994; Cavalli
et al., 2000; Chen et al., 2004; Leonetti et al., 2004; Cavalli et al., 2005; Schuster et al., 2006;
Nagar et al., 2008; Castellano et al., 2008; Nagar et al., 2009; Karkola & Wahala, 2009; Petkov et
al., 2009; Nagar & Saha, 2010a; Nagar & Saha, 2010b; Nagar & Saha, 2010c; Roy & Roy, 2010b;
Sun et al., 2010; Froufe, Abreu, & Ferreira, 2011; Narayana et al., 2012; Nantasenamat et al., 2013)
were performed, structure based as well as ligand based molecular modeling techniques can be used
to identify or discover new potential leads with less adverse effects in future that may be beneficial
as far as the breast cancer mortality rate is concerned. The chapter highlights the LBDD as well
as SBDD studies of NSAIs that can be utilized to design novel anti-aromatase leads useful for the
treatment of breast carcinomas. Before discussing the various modeling strategies, the overview of
breast cancer and its treatment, and chemistry and functionalities of aromatase enzyme for development of anti-aromatase drugs against breast cancer have been highlighted.
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Figure 2. Rational drug design approaches
BREAST CANCER AND ITS TREATMENT
Various factors, such as age, family history, early menarche, late menopause, postmenopausal obesity,
use of estrogen and progestin menopausal hormones, alcohol and physical inactivity may be responsible
for developing breast cancers. Inheritance of an inactivating mutation in one of the familial breast cancer genes, like BRCA1, BRCA2, CHEK2, p53 and ATM may be the strongest risk factor for the breast
cancer, contributing 5% of the breast cancer cases. The second highest risk factor is age. Three-quarter
of breast cancer cases (< 5%) is observed in postmenopausal woman less than 40 years of age. But the
highest incidence of mortality is observed in women between the age of 34 and 54. The other risk factors include exposure of estrogens, absence of lactation, hormonal therapy and use of oral contraceptive
pills (May, 2014; Westley and May, 2013; McCullough et al., 2012; Allen et al., 2009). Nevertheless,
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Ligand- and Structure-Based Drug Design of NSAIs in Breast Cancer
the risk of breast cancer may be observed in diabetic conditions like high circulating insulin-like growth
factor-1 (IGF-1) and low serum insulin-like growth factor binding protein 3, though exercise may reduce
the risk of breast cancer. The chance of developing invasive breast cancer is strongly influenced by the
extent of spread of cancer when it is first diagnosed. The American Joint Committee on Cancer (AJCC)
classified tumors on the basis of tumor size and the propagation within the breast and nearby organs (T)
and involvement of lymph node (N) as well as the presence or absence of different metastases in distant
organs (M) (AJCC Cancer Staging Manual, 2002). If T, N and M are determined, stages of I, II, III, and
IV are assigned, where stage I is an early stage and stage IV is the most advanced.
The early detection of breast cancer uses mammography, clinical breast examination (CBE) and
magnetic resonance imaging (MRI). Mammography may be able to detect about 80-90% of the breast
cancer (Michaelson, Satija, & Moore, 2002). For women aged 40 and above, annual CBE may be an
important complement to mammography. A small percentage of breast cancers may be missed during
mammography can be detected in CBE. The shape, texture, location of lumps and if any skin color changes
are observed during CBE. In MRI, magnetic fields are used instead of X-ray mammography. It generates detailed cross-sectional images of breast tissue. As far as the breast cancer treatment is concerned,
it includes both local and systemic therapy to get rid of tumor as completely as possible and to prevent
its recurrence. Local therapy includes surgery and radiation therapy. In lumpectomy, only cancerous
tissues along with some portion of normal tissues are removed. In mastectomy, removal of complete
breast occurs. Lumpectomy followed by radiation may affect the same expected long time survival rate
as in mastectomy (Fisher, Anderson, & Bryant, 2002). In both lumpectomy and mastectomy, removal
of axillary lymph nodes is done to determine the spreading beyond breast. The presence of cancerous
lesions in lymph node helps to determine subsequent therapy. Sentinel lymph node biopsy reduces the
need for full axillary lymph node dissections in majority of women with no evidence of lymph node enlargement before therapy (Lyman, Giuliano, & Somerfield, 2005). Radiation therapy destroys cancerous
cells after or before surgery in the breast, chest wall and or underarm area (Early Breast Cancer Trialists’ Collaborative group, 2000). Radiation therapy depends on the type and stage as well as location of
the tumor being treated. Apart from the local therapy, systemic therapy includes biological therapy and
chemotherapy as well as hormone therapy. Systemic treatment with anticancer drugs prior to surgery is
a neoadjuvant therapy. This helps in shrinkage of tumor which relieves the stress of surgical removal. In
adjuvant therapy, a systemic treatment is given to the patients after surgery. This therapy is more effective
in terms of survival, disease progression and distant recurrence (Mauri, Pavlidis, & Loannidis, 2005).
Approximately, about 15-30% of breast cancers are related to overproduction of the growth promoting
protein ‘Human Epidermal Growth Factor Receptor 2’ (HER2/neu). It is also known as ErbB2 protein.
It gives higher aggressiveness in breast cancers. It belongs to ErbB2 protein family or epidermal growth
factor receptor (EGFR) family. It is also known as CD340 (cluster of differentiation 340) and p185. It is
encoded by ErbB2 gene (Gligorov & Lotz, 2008). Overexpression of this receptor is associated generally
with increased disease recurrence as well as worse prognosis. Since the prognostic role of the receptor
and its ability to predict response against trastuzumab (herceptin), breast tumors are checked regularly
for overexpression of HER2/neu [since the oncogene ‘neu’ is derived from a rodent gliboblastoma cell
line (a neural tumor), it is termed as ‘neu’]. HER2 is named on the basis of its similar structure to human epidermal growth factor receptor 1 (HER1). Similarly, ErbB2 is termed for its similarity to ErbB
(avian erythroblastosis oncogene B). It is found to encode EGFR. Gene cloning study showed that neu
and HER2 as well as ErbB2 are same protein. The HER2 is co-localized and therefore, co-amplified
with the gene GRB7. The GRB7 is a proto-oncogene found active in breast, gastric and esophageal
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