Design, ADMET, PASS Prediction and Molecular Docking Studies of Novel pyrazolo[3,4-d]pyrimidines for Prospective of Anti-Cancer Agents

The increased burden of cancer disease globally arouses the urgent need for the development of novel chemical agent with improved efficacy and potency which can provide selective therapeutic outcome to an individual cancer patient. In this connection the in-silico designing of novel scaffolds are greatly helpful evading the need for synthesizing and evaluating the series of large number compounds. We have constructed novel pyrazolopyrimidines with reference to existing fused pyrimidine standards like central aromatic heterocycles, spacers, hydrophobic heads and tails. We examined for the nature and biochemical targets, ADMET evaluations using various online tools and molecular docking analysis through Schrodinger suite studied binding affinities with reference to standards as well as co-crystals. We designed pyrazolopyrimidines 7a-j and 12a-j & molecular docking studies revealed that few were potential candidates compared to standard scores against various Ptarget kinases. The hydroxyl moiety in 7b & 7d, hydroxyl in 7e with 4-bromo showed more bonding affinity towards targets and remaining compounds produced mild to moderate affinities against various targets. GLU339, GLU51, LEU83, SER345, ASP404, ASN391and ASP348 are major residues for H-bonding interactions, PHE80, LEU83, GLN275 influenced hydrophobic bonding and ASP404 for nitro group, GLU339 for hydroxyl group, LYS89 for methoxy groups are key residues in binding affinity. We also identified the key residues of target proteins involved in the interaction with ligands at the active pocket. We believe that these results could benefit the future development of anticancer scaffold containing pyrazolopyrimidine motifs in the core structure.