Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of...

The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling cascades in a wide variety of cancers. In the last 15 years, there has been an increase in the search for selective inhibitors of the four class I isoforms of PI3K, as they demonstrate better specificity and reduced toxicity in comparison to existing inhibitors. A ligand-based and target-based rational drug design strategy was employed to build a virtual library of 105 new compounds. Through this strategy, the four isoforms were compared regarding their activity pocket availability, amino acid sequences, and prone interactions. Additionally, a known active scaffold was used as a molecular base to design new derivatives. The virtual screening of the resultant library toward the four isoforms points to the obtention of 19 selective inhibitors for the PI3Kα and PI3Kγ targets. Three selective ligands, one for α-isoform and two for γ-isoform, present a ∆ (∆G_binding) equal or greater than 1.5 Kcal/mol and were identified as the most promising candidates. A principal component analysis was used to establish correlations between the affinity data and some of the physicochemical and structural properties of the ligands. The binding modes and interactions established by the selective ligands in the active centre of the α and γ isoforms of PI3K were also investigated. After modelling studies, a synthetic approach to generate selective ligands was developed and applied in synthesising a set of derivatives that were obtained in good to excellent yield.