Evaluation and Optimisation of in silico

Breast cancer is defined as the uncontrolled growth of neoplastic cells in breast tissues, which can be environmentally and or hormonally induced. This project uses GW5638, a selective oestrogen receptor modulator with clinical potential in the management of tamoxifen-resistant breast cancer as lead molecule in the in silico drug design of novel antagonists. This molecule is particularly interesting due to its ability to induce a hitherto undocumented conformational change in receptor structure, delineating a new ligand binding domain (LBD) conformation in which helix 12 occupies a distinct spatial orientation. Protein data bank crystallographic deposition 1R5K describing the holo GW5638:oestrogen receptor complex was identified and mutual affinity calculated in X-Score ® v1.3 for baseline affinity establishment. In phase 1 of the study, GW5638 was edited computationally and five seed structures were generated. Each seed sustained molecular growth using the GROW algorithm of LigBuilder ® v2 at pre-selected loci considered as non-critical to binding and clinical efficacy on the basis of SAR studies.