Study of Additional Interactions of Heterodimeric GW7604 Derivatives at the Coactivator Binding Site through Pharmacophore Modeling

Abstract

Breast cancer is still the most common cancer in women worldwide, affecting one in eight women in high-income countries, and the incidence is further increasing. Endocrine therapy, including aromatase inhibitors or selective estrogen receptor modulators (SERMs)/selective estrogen receptor down-regulators (SERDs), consequently represents an indispensable treatment opportunity. Unfortunately, acquired endocrine resistance is an inevitable issue, which manifests after prolonged therapy. Consequently, developing a novel drug for the treatment of breast cancer is need of the hour. But it is an established fact that designing or repurposing a drug using ‘trial and error’ approach is a tricky, long, expensive and could be a failure in clinical stage. Hence, there is a need to employ alternative approaches like computer aided drug design (CADD) to overcome these shortcomings of conventional approach. Recently, CADD has gained a high popularity among drug designers and medicinal chemists due to several advances associated with it. Pharmacophore modeling is an efficient and useful approach to identify important patterns in a series of molecules for optimizations. Hence, in this analysis, an attempt is made to develop consensus pharmacophore model of heterodimeric GW7604 derivatives using alignment approach. The dataset consists of fourteen heterodimeric GW7604 derivatives exhibiting the binding activity in a transactivation assay ERα and ERβ to the coactivator binding site. The heterodimeric GW7604 derivatives possess good variation in substation pattern like the presence of different diaminoalkane spacer and CABS binder. The consensus pharmacophore model revealed the importance of structural features and their correlation with the biological activity.