Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A

Title:Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A

Volume: 14 Issue: 10

Author(s): Nivedita Singh, Parameswaran Saravanan, M.S. Thakur and Sanjukta Patra*

Affiliation:

• Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039,India

Keywords: BAY73-6691, cGMP, IBMX, molecular docking, PDE9A, PF04447943, xanthine.

Abstract: 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.

Cite this article as:

Singh Nivedita, Saravanan Parameswaran, Thakur M.S. and Patra Sanjukta*, Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A, Letters in Drug Design & Discovery 2017; 14 (10) . https://dx.doi.org/10.2174/1570180813666161102125423

DOI https://dx.doi.org/10.2174/1570180813666161102125423	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X