Synthesis and inverse virtual screening of new bi-cyclic structures towards cancer-relevant cellular targets

Abstract

We report here synthetic approaches to access new classes of small molecules based on three heterocyclic scaffolds, i.e. 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione, 1,8-naphthyridin-4(1H)-one and 4H-pyrido[1,2-a]pyrimidin-4-one. The bi-cyclic structure 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione is a new heterocycle, described here for the first time. In silico methodologies of inverse virtual screening have been used to preliminary analyse the molecules, in order to explore their potential as hits for chemical biology investigations. Our computational study has been conducted with 43 synthetically accessible small molecules towards 31 cellular proteins involved in cancer pathogenesis. Binding energies were quantified using molecular docking calculations, allowing to define the relative affinities of the ligands for the cellular targets. Through this methodology, 16 proteins displayed effective interactions with distinct small molecules within the matrix. In addition, 23 ligands have demonstrated high affinity for at least one cellular protein, using as reference the co-crystallised ligand in the X-ray structure. The evaluation of ADME and drug score for selected hits also highlights that these new molecular series can serve as sources of lead candidates for further structure optimisation and biological studies.