3D-QSAR Study of Potent Inhibitors of Phosphodiesterase-4 Using a CoMFA Approach

Zhaoqi Yang,Pinghua Sun

doi:10.3390/i8070714

Abstract

Phosphodiesterase-4 (PDE4) plays an important role in treatment of asthma andchronic obstructive pulmonary disease. Thirty-one analogs displaying variable inhibition ofPDE4 were selected to develop models for establishing three-dimensional quantitativestructure-activity relationships (3D-QSAR). Comparative molecular field analysis(CoMFA) was conducted on the group of analogs to determine the structural requirementsfor potency in inhibiting PDE4. The resulting model exhibited good q2 and r2 values up to0.741 and 0.954 for CoMFA. The contributions from the steric and electrostatic fields were0.915 and 0.085 respectively. The 3D-QSAR model should be very useful for design ofnovel PDE 4 inhibitors.

Highlights

Asthma and chronic obstructive pulmonary disease (COPD) are the two most prevalent chronic airway diseases
PDE4 plays a significant role in modulating the activity of cAMP, an important second messenger that mediates the relaxation of airway smooth muscle and suppresses inflammatory cell function, thereby attenuating the inflammatory response [7]
We present here our 3D-QSAR studies using Comparative molecular field analysis (CoMFA) method on a training set of 5,6-dihydro(9H)-pyrazolo-[4,3-c]-1,2,4-triazolo-[4,3-α]-pyridine derivatives as PDE4 inhibitors by considering the steric and electrostatic influences

Summary

Introduction

Asthma and chronic obstructive pulmonary disease (COPD) are the two most prevalent chronic airway diseases. Phosphodiesterase-4 (PDE4) is a key enzyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes, as well as areas in the brain and airway smooth muscle [5,6]. PDE4 plays a significant role in modulating the activity of cAMP, an important second messenger that mediates the relaxation of airway smooth muscle and suppresses inflammatory cell function, thereby attenuating the inflammatory response [7]. Increasing the intracellular concentration of cAMP in the airway tissues and cells suppresses inflammatory cell function and should be beneficial for treatment of asthma and COPD [8]. The model deduced from this investigation provides underlying structural requirements and good predictive ability, which could aid new PDE4 inhibitors prior to their synthesis

Molecular Modeling

CoMFA analysis

Results and Discussion