Background: In recent times, computer aided methodologies have received broad
attention in drug development. These studies have improved the accuracy and shortened the time
frame to identify suitable drug candidates from large datasets. Xanthine is a plant alkaloid which also
acts as an intermediate product on the pathway of purine degradation. Xanthine acts as scaffold for
various natural and synthetically derived bioactive molecules.
Objective: The present work aims to screen xanthine derivatives targeting phosphodiesterase 9A
(PDE9A), one of the most important regulatory protein of signal transduction.
Method: In silico approach such as Virtual screening, molecular docking and molecular dynamic
was attempted to screen a repertoire of 2055 xanthine derivatives extracted from ZINC database
against PDE9A. The potency of the resultant screened compound was finally validated by
spectrophotometric malachite green inhibition assay.
Results: Preliminary virtual screening narrowed down the compounds to a list of 10 which is
followed by a second round of stringent screening using molecular docking approach. Top four hits
were selected for thorough interaction analysis with PDE9A. The molecular docking analysis of best
ranked compound, ZINC62579975 (-12.59) revealed its potential to establish essential chemical
interactions with inhibition determining key residues in the PDE9A active site. The stability of
ZINC62579975 in PDE9A was further validated by 6 ns molecular dynamic simulation studies. The
in vitro malachite spectrophotometric assay confirmed the bioactive potential of the above
compound. Comparative inhibition studies asserted more potency of ZINC62579975 towards
PDE9A (46.96 ± 1.78 µM) than PDE5A (61.023 ± 1.71 µM) and PDE4D (70.04 ± 1.98 µM).
Conclusion: The entire study validates ZINC62579975 as a potent candidate molecule for PDE9A
inhibition. The present study provides a roadmap for future drug designing of more potent xanthine
derivatives. This study also explores the potential of xanthine scaffold in future drug development