Background: Phosphodiesterases 9A (PDE9A) is one of the prominent regulating enzymes
of the signal transduction pathway having highest catalytic affinity for second messenger, cGMP.
When the cGMP level is lowered, an uncontrolled expression of PDE9A may lead to various
neurodegenerative diseases. To regulate the catalytic activity of PDE9A, potent inhibitors are needed.
Objective: The primary objective of the present study was to develop new xanthine based inhibitors
targeting PDE9A. This study was an attempt to bring structural diversification in PDE9A inhibitor development
because most of the existing inhibitors are constructed over pyrazolopyrimidinone scaffold.
Methods: Manual designing and parallel molecular docking approach were used for the development
of xanthine derivatives. In this study, N1, N3, N9 and C8 positions of xanthine scaffold were selected as
substitution sites to design 200 new compounds. Reverse docking and pharmaceutical analyses were
used for final validation of most promising compounds.
Results: By keeping free energy of binding cut-off of -6.0 kcal/mol, 52 compounds were screened. The
compounds with substitution at N1, N3 and C8 positions of xanthine showed good occupancy in PDE9A
active site pocket with a significant interaction pattern. This was further validated by screening
different factors such as free energy of binding, inhibition constant and interacting active site residues
in the 5Å region. Substitution at C8 position with phenyl substituent determined the inhibition affinity
of compounds towards PDE9A by establishing a strong hydrophobic - hydrophobic interaction. The
alkyl chain at N1 position generated selectivity of compounds towards PDE9A. The aromatic fragment
at N3 position increased the binding affinity of compounds. Thus, by comparative docking study, it was
found that compound 39-42 formed selective interaction towards PDE9A over other members of the
PDE superfamily.
Conclusion: From the present study, N1, N3 and C8 positions of xanthine were concluded as the best
sites for substitution for the generation of potent PDE9A inhibitors.
QM/MM study of l-lactate oxidation by flavocytochrome b2
