Surface Binding Energy Landscapes Affect Phosphodiesterase Isoform-Specific Inhibitor Selectivity

Qing Liu,Andreas Herrmann,Qiang Huang

doi:10.1016/j.csbj.2018.11.009

Abstract

As human phosphodiesterase (PDE) proteins are attractive drug targets, a large number of selective PDE inhibitors have been developed. However, since the catalytic sites of PDE isoforms are conserved in sequence and structure, it remains unclear how these inhibitors discriminate PDE isoforms in a selective manner. Here we perform long-time scale molecular dynamics (MD) simulations to investigate the spontaneous association processes of a highly selective PDE2A inhibitor (BAY60–7550) with the catalytic pockets of six PDE isoforms. We found that the free-energy landscapes of PDE:BAY60–7550 interactions on the PDE surfaces are very different between various PDE isoforms; and the free-energy landscape of PDE2A forms a favorable low-energy pathway that not only drives BAY60–7550 toward the target binding site, but also guides BAY60–7750 to adopt its native binding conformation known from crystal structure. Thus, this study reveals that the inhibitor interactions with the PDE surface residues play an important role in its high selectivity for PDE2A, and thereby provides new fundamental insights into the PDE isoform-specific inhibitor selectivity.

Highlights

Human phosphodiesterase (PDE) family consists of 11 subfamilies and expressed in a tissue-specific manner [1]
We used the root-mean-square deviation (RMSD) to evaluate the similarity between the PDE-bound conformations of BAY60– 7550 in the molecular dynamics (MD) simulations and the native pose [11]
We have performed unbiased MD simulations to successfully capture the spontaneous associations of BAY60–7550 with the catalytic pockets of the 6 PDE isoforms

Summary

Introduction

Human phosphodiesterase (PDE) family consists of 11 subfamilies and expressed in a tissue-specific manner [1]. In the past two decades, many PDE inhibitors have been developed, including sildenafil (PDE5 inhibitor) [5], roflumilast (PDE4 inhibitor) [6], and milrinone (PDE3 inhibitor) [7], which were approved for the treatments of erectile dysfunction [8], chronic obstructive pulmonary disease (COPD) [6], and congestive heart failure [9], respectively. Those PDE inhibitors could cause side effects during their clinical treatments. Because the binding selectivity of the PDE inhibitors is crucial for the development of safe drugs, it is necessary to fully understand the structural origins of the PDE inhibitor selectivity

Methods

Results

Conclusion