Design and identification of steroid receptor co-activator modulators for the management of Neoplastic Disease

Abstract

The Steroid Receptor Co-activator (SRC) is overexpressed in several cancer types such as colon, breast, and brain cancer. Wang et al. hypothesised that the overstimulation of the SRC might be able to disrupt tumour homeostasis. This results in tumour stress and tumour cell mortality. MCB-613 is a cytotoxic small molecule stimulator that overstimulates the transcriptional activity of the whole SRC family proteins. The small agonist molecule MCB-613 was docked into the apo SRC ligand binding pocket (LBP) obtained from Protein Data Bank (PDB) crystallographic deposition 2SRC. Conformational analysis was performed. The molecule with the lowest ligand binding energy (LBE) (Kcal/mol) and highest ligand binding affinity (LBA) (pKd) was identified as the optimal conformer, and its critical interactions with the SRC were used in a dual approach of virtual screening (VS) and de novo ligand growth. The modelled seed fragments generated by the de novo approach were planted within the generated SRC_LBP map and fragment growth was performed which resulted in a cohort of structures. A consensus pharmacophore was modelled and used for analog identification using MCB-613 best conformer. A protomol was generated and structures were identified for virtual screening. De novo growth yielded a total of 638 molecules, 405 of which were Lipinski Rule compliant. The VS approach yielded a total of 25 hits. The molecules which were designed de novo have an affinity superior to that of the endogenous ligand implying that these molecules would displace the endogenous antagonist in vivo, and that they could potentially therefore exert the desired super agonist effect. The optimal hits obtained through VS are the highest affinity molecules with physicochemical parameters which most strongly adhere to the rule of 3 for lead like structures and which consequently leave most room for further optimisation.