Molecular modeling study of binding to the catalytic site of PDE4 enzymes by a novel class of inhibitors

Abstract

AbstractCyclic nucleotide phosphodiesterases (PDEs) comprise a superfamily of enzymes that hydrolyze the second messengers adenosine and guanosine 3′,5′‐cyclic monophosphate (cAMP and cGMP) to their noncyclic nucleotides (5′‐AMP and 5′‐GMP). Selective inhibitors of all 11 gene families of PDEs are being sought based on the different biochemical properties of the different isoforms, including their substrate specificities. The PDE4 gene family consists of cAMP‐specific isoforms; selective PDE4 inhibitors such as rolipram have been developed, and related agents are used clinically as anti‐inflammatory agents for asthma and COPD. The known crystal structures of PDE4 bound with rolipram and IBMX have allowed us to define plausible binding orientations for a novel class of benzylpyridazinone‐based PDE4 inhibitors represented by EMD 94360 and EMD 95832 that are structurally distinct from rolipram. Molecular mechanics modeling with autodocking is used to explore energetically favorable binding orientations within the PDE4 catalytic site. We present two putative orientations for EMD 94360/95832 inhibitor binding. Our estimated interaction energies for rolipram, IBMX, EMD 94360, and EMD 95832 are consistent with the experimental data for their IC50 values. Key binding residues and interactions in these orientations are identified and compared with known binding motifs proposed for rolipram. The experimentally observed improved strength of inhibition exhibited by this novel class of PDE4 inhibitors is explained by the molecular modeling reported here. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005