Evaluation and Optimisation of in silico. Designed Oestrogen Receptor Modulators for the Management of Breast Cancer

      Аннотация: 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.

Ключевые слова: evaluation, Optimisation, silico, oestrogen, Receptor Modulators, Management, breast cancer