‘In silico’ design and validation of novel cyclin dependent kinase (CDK) receptor inhibitors, using the palbociclib scaffold, a molecule for the management for breast cancer as a lead

Abstract

Cyclin Dependent Kinases 4 and 6 (CDK4/6) are crucial in promoting cell growth and maturation during mitosis through interaction with Cyclin D and subsequent phosphorylation of the Retinoblastoma Protein. Palbociclib disrupts cancer proliferation in locally advanced or metastatic breast cancer by firmly binding to CDK4/6 and arresting the ensuing cascade. The objective of this study was to probe the CDK6 ligand binding pocket (LBP) using the Palbociclib scaffold for the in silico identification and design of lead molecules capable of high affinity modulation of the target. PDB crystallographic depositions 5L2I and 5L2S describing the bound coordinates of Palbociclib and Abemaciclib with the CDK6 receptor respectively were read into LigandScout® . The generated consensus pharmacophore was used as a query in ZINCPharmer® and the Rule of 3 compliant hits were docked into a modelled ProtoMol describing the CDK6_LBP as generated in Sybyl® -X v.2.1.1. The Ligand Binding Affinity (LBA) of these hits was calculated. In the de novo approach, 2-D topology maps describing the atomic interactions of Palbociclib with the targets guided the modelling of 5 seeds in SYBYL® -X v.2.1.1. Each seed was docked into the modelled CDK6_LBP in LigBuilder® for novel molecular growth. The resultant molecular cohorts were analysed for Lipinski-rule compliance and their LBA determined. Two molecules resulting from the de novo approach were selected for the modelling of a hybrid molecule with a high affinity and a low binding energy. Conformational analysis of the hybrid molecule was carried out in SYBYL® -X to determine the conformer that best fits the receptor’s bioactive site. Results from the Virtual Screening (VS) and de novo processes were compared –and the optimal structures were selected for further optimisation, validation, and in vivo signalling assays. The best conformer of the modelled hybrid molecule was identified and considered as a lead for optimisation.