Cyclic nucleotide phosphodiesterases (PDE’s) play a key role in regulating the levels of the ubiquitous second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). There are 11 PDE human families that, therefore, provide a handle for control of an array of biochemical pathways throughout the body and have proven to be effective drug targets for numerous diseases such as: erectile dysfunction and pulmonary hypertension (PDE4, PDE5, PDE6 and probably PDE11); intermittent claudication, thrombocythemia (PDE3); vascular disease (PDE1); Central Nervous System (CNS) disorders (PDE9 and PDE10); cognitive disorders (PDE2); treatment for drug addiction as cocaine and methamphetamine (PDE7). On the other hand, all the 11 PDE’s share a conserved catalytic domain with ~300 amino acids and 2 divalent ions (Zn2+ and Mg2+). Hence, achieving selectivity for a specific family, thus reducing side effects, is not trivial. In this retrospective study, we show how FEP+ can reproduce selectivity for two pairs of PDE families that share over 50% of similarity in the catalytic domain: PDE9 vs PDE1 and PDE5 vs PDE6. In addition, since there aren’t co-crystal structures available of PDE1 and PDE6 in complex with inhibitors yet, we show how we can accurately reproduce selectivity through FEP+ also on homology models with a very good agreement with the experimental data. Given the highly conserved catalytic domain across PDE’s, the purpose of validating this FEP+ selectivity protocol on those 2 sets of PDE families is to create a robust and relatively fast selectivity method that can be extended to the other PDE families and embedded in the lead optimization process of a drug discovery program. The prospective application of this approach is the theme of our next work.

Retrospective study to assess selectivity among phosphodiesterases (PDE's) families using FEP+

256th National Meeting (2018)

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