Nivedita Singh, Swagata Patra and Sanjukta Patra* Pages 1 - 11 ( 11 )
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 process.
Xanthine, Molecular docking, Virtual screening, PDE9A, ADME, Inhibition
Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039