De Nove Ligand Design of Selective Estrogen Receptor Modulators (SERMs)Surachai Joomprabutra
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Estrogen controls various physiological processes such as sexual differentiation and development, cardiovascular system, and bone health. The reduction of estrogen in the body like in postmenopausal women leads to an incidence of coronary heart disease and lost of bone mineral density. However, estrogen use in hormone replacement therapy is associated with an increased risk of uterine and breast cancer which limits its use as a replacement in postmenopausal women. The finding of group of estrogen receptor ligands having ability to behave as partial or full agonists in some tissues while behaving as antagonists in others, they are called selective estrogen receptor modulators (SERMs). In this study, preliminary SERMs pharmacophore was developed based on the different in mode of binding of ligands. This pharmacophore was used in the De Novo ligand design process to generate the candidates. Candidates were first evaluated by their binding affinity and their bioavailability via their compliance to Lipinski’s rule of five. In this preliminary study, three candidates were selected based on their conforming to generated SERMs’s pharmacophore. They were further analyzed for their inhibition constant and their ability to select the binding mode of raloxifene over that of 4OH-tamoxiphen. All candidate have shown inhibition constant in the micromolar and submicromolar range while one of the candidate shows selectivity to the prefer binding mode better than that of raloxifene. These results prove the validity of the generated pharmacophore. Further enhancement of current pharmacophore aiming for the next generation of SERMs ligands which have higher potency and tissue selectivity.
Keyword:
De Novo Ligand ,SERMs,sexual differentiation ,cardiovascular system, postmenopausal women ,uterine cancer, breast cancer, raloxifene ,tamoxiphen
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