Phosphodiesterase-5 (PDE5) inhibitors can be used as clinical agents for the treatment of erectile dysfunction and pulmonary hypertension. A series of aryl-chromeno-pyrrol derivatives were previously identified as PDE5 inhibitors in our lab. Herein, these molecules were subjected to 3D-QSAR analysis with CoMFA and CoMSIA methods to gain deeper insight into the structural requirements for their bioactivities. Receptor- and ligand-based alignment were used and compared to find the alignment-related factors that affect the accuracy of QSAR models. The receptor-based CoMFA and CoMSIA models, which were generated by superimposing the docking conformations directly in the protein binding site, gave more significant results for 38 training set compounds and 5 test set molecules. Comparison of the two alignments revealed that spatial arrangement of the ligands is the principal factor in determining the reliability of the 3D-QSAR models. Detailed analysis of the receptor-based CoMSIA-SE contour maps provided much helpful information to improve the bioactivities of aryl-chromeno-pyrrol analogs as PDE5 inhibitors.

3D-QSAR modeling of Phosphodiesterase-5 inhibitors: evaluation and comparison of the receptor- and ligand-based alignments

Innovative screening for functional improved aromatic amine derivatives: Toxicokinetics, free radical oxidation pathway and carcinogenic adverse outcome pathway.

Neurodegenerative diseases are pathological disorders inducing a gradual loss of neuronal functionality presenting a multifactorial character. Among them, Alzheimer’s disease (AD) causes the most well-known type of dementia and one of the major representatives. Due to the multifactorial etiology of AD, pleiotropic treatments are getting increasing importance. Phosphodiesterases (PDEs) are treated as molecular targets for many pathological situations. Neurodegenerative manifestations are among them. Regulation of the concentration of cAMP and/or cGMP is related to the inhibition of PDEs located in the human brain. In this chapter, we will discuss the results of computational modeling studies on PDE inhibitors as anti-Alzheimer agents. Hydrogen bonds, π–π stacking, and volume are important for the interaction of the molecules with the catalytic site of PDEs. 

Laiyou Wang

Papers

Docking-based 3D-QSAR Studies of Phosphodiesterase 9A Inhibitors