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

作者：Cichero Elena; Bruno Olga; Fossa Paola^*

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, 27(5): 730-743.

DOI：10.3109/14756366.2011.611136

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

Tetrahydro-beta-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(ncv) 2 = 0.96, r(cv)(2) = 0.688, SEE = 0.248, F = 104.800, and r(pred)(2) = 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.

• 出版日期2012-10