Docking-based CoMFA and CoMSIA analyses of tetrahydro-β-carboline derivatives as type-5 phosphodiesterase inhibitors

Abstract

Tetrahydro-β-carboline derivatives (THBCs) have been identified as a class of potent Type-5 Phosphodiesterase (PDE5) inhibitors, showing benefits for the treatment of erectile dysfunction and also bearing anticancer properties. A computational strategy based on molecular docking studies, followed by docking-based Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA), has been used to elucidate the atomic details of the PDE5/THBC interactions and to identify the most important features impacting the THBC PDE5 inhibitory activity. The final CoMSIA model resulted to be the more predictive, showing r_ncv² = 0.96, r_cv² = 0.688, SEE = 0.248, F = 104.800, and r²_pred = 0.78. The results allowed us to obtain useful information for the design of new THBC analogues, potentially acting as PDE5 inhibitors, and to predict their potency prior to synthesis.

Keywords::

• Phosphodiesterases
• PDE5
• tetrahydro-β-carbolines
• docking
• CoMFA
• CoMSIA