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

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 rncv2 = 0.96, rcv2 = 0.688, SEE = 0.248, F = 104.800, and r2pred = 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.

 

Elena Cichero, Olga Bruno, Paola Fossa
October 1, 2012
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