Docking and quantitative structure-activity relationship of bi-cyclic heteroaromatic pyridazinone and pyrazolone derivatives as phosphodiesterase 3A (PDE3A) inhibitors.

Camila Muñoz-Gutiérrez,Daniela Cáceres-Rojas,Eduardo Fuentes,Francisco Adasme-Carreño,Iván Palomo,Julio Caballero

doi:10.1371/journal.pone.0189213

Abstract

PDE3s belong to the phosphodiesterases family, where the PDE3A isoform is the major subtype in platelets involved in the cAMP regulation pathway of platelet aggregation. PDE3A inhibitors have been designed as potential antiplatelet agents. In this work, a homology model of PDE3A was developed and used to obtain the binding modes of bicyclic heteroaromatic pyridazinones and pyrazolones. Most of the studied compounds adopted similar orientations within the PDE3A active site, establishing hydrogen bonds with catalytic amino acids. Besides, the structure-activity relationship of the studied inhibitors was described by using a field-based 3D-QSAR method. Different structure alignment strategies were employed, including template-based and docking-based alignments. Adequate correlation models were obtained according to internal and external validations. In general, QSAR models revealed that steric and hydrophobic fields describe the different inhibitory activities of the compounds, where the hydrogen bond donor and acceptor fields have minor contributions. It should be stressed that structural elements of PDE3A inhibitors are reported here, through descriptions of their binding interactions and their differential affinities. In this sense, the present results could be useful in the future design of more specific and potent PDE3A inhibitors that may be used for the treatment of cardiovascular diseases.

Highlights

IntroductionPhosphodiesterases (PDEs) are enzymes which degrade cAMP and/or cyclic guanosine monophosphate (cGMP).[1,2,3] They are classified into 12 PDE families, where several of them are cAMP-specific enzymes, others are cGMP-specific enzymes, and others use both cyclic nucleotides as substrate.[4] In particular, platelets contain three classes of PDEs: PDE2, PDE3, and PDE5
Phosphodiesterases (PDEs) are enzymes which degrade cAMP and/or cyclic guanosine monophosphate.[1,2,3] They are classified into 12 PDE families, where several of them are cAMP-specific enzymes, others are cGMP-specific enzymes, and others use both cyclic nucleotides as substrate.[4]
Two large regions missing in the PDE3B crystal, residues 779–795 and 1028–1066 were refined via restrained molecular dynamics (MD) simulations; they are shown in Fig 2A as L1 and L2, respectively

Summary

Introduction

Phosphodiesterases (PDEs) are enzymes which degrade cAMP and/or cyclic guanosine monophosphate (cGMP).[1,2,3] They are classified into 12 PDE families, where several of them are cAMP-specific enzymes, others are cGMP-specific enzymes, and others use both cyclic nucleotides as substrate.[4] In particular, platelets contain three classes of PDEs: PDE2, PDE3, and PDE5. PDE3, which hydrolyzes both cAMP and cGMP, is the most abundant PDE in platelets. It exhibits low Km for cAMP (0.2–0.5 μM) and is competitively inhibited by cGMP.

Methods

Results

Conclusion