Design and identification of Beta cell Lymphoma-2 (BCL-2) receptor modulators for the management of leukaemia and solid tumours

Abstract

Literature indicates that navitoclax and venetoclax have potential in the management of malignant tumours and leukaemia. These molecules mimic the structure of proapoptotic proteins and act as antagonists to prosurvival receptors found on the mitochondria of cancerous cells. This at the expense of unacceptable side effects including thrombocytopenia. The Beta Cell Lymphoma-2 (BCL-2) receptor regulates apoptosis and is a target in the design of tumour mitigating drugs. The navitoclax and venetoclax antagonist scaffolds will be used as lead molecules for the in silico identification and design of improved high affinity antagonists. Virtual screening (VS) (ligand based drug design) and de novo (structure based drug design) were the basis of the methodology. In VS, navitoclax was co-crystallised with the BCL-2 receptor as described in protein data bank (PDB) 4LXD (Souers et al., 2013) and extracted from the ligand binding pocket (LBP). Venetoclax was modelled in three dimensions (3D) and docked in the BCL-2 LBP. Conformational analysis was used to identify the optimally binding scaffold of venetoclax which together with the bioactive conformation of navitoclax, were used to probe the BCL-2 LBP. An average consensus pharmacophore representing an average of the optimal venetoclax conformer and the bioactive conformation of navitoclax was submitted as a query to a database in order to identify analogous molecules. These hits would by inference be able to forge analogous atomic interactions within the BCL-2 LBP, consequently potentially eliciting a similar clinical response. In the de novo approach, a two dimensional (2D) map of the interaction between the ligand navitoclax and the BCL-2 LBP was used to identify the fundamental atoms required for this interaction to occur. Seed structures were modelled from a pharmacophore that venetoclax and navitoclax share through a fragmentation exercise. These were planted into the BCL-2 LBP, and de novo growth was allowed within its confines. The optimal structures obtained will be suggested for optimisation, synthesis and in vitro validation to assess potential clinical efficacy.