Subtype selectivity in phosphodiesterase 4 (PDE4): a bottleneck in rational drug design

Current Pharmaceutical Design
P SrivaniG Narahari Sastry

Abstract

Subtype selectivity of phosphodiesterase 4 (PDE4) has been proposed to be the most salient feature for the development of drugs for asthma and inflammation. The present review provides an account of various strategies to overcome the side effects of the PDE4 inhibitors. Subtype selectivity and recent developments of molecular modeling approaches towards PDE4 were addressed using QSAR and docking, followed by a detailed structural analysis of more than three dozen available X-ray structures of PDE4B and PDE4D. Usually, the lack of a 3-dimensional structure of a target protein is a bottleneck for rational drug design approaches. However, in this case the availability of 39 X-ray structures along with co-crystals has not improved the therapeutic ratio of drugs through rational drug design approaches. The investigation of structures led to find significant variations in the M-loop region, which is the integral part of the active site of PDE4B and PDE4D. These differences can be accounted for by varying conformation of the Pro(430) residue and a Thr(436)/Asn(362) mutation in the M-loop that causes variations in adjacent residue properties and also the pattern of hydrogen-bonding interactions. The impact of the M-loop region on inhib...Continue Reading

Citations

May 9, 2012·Journal of Molecular Modeling·Mohammed H Bohari, G Narahari Sastry
Feb 7, 2012·Journal of Molecular Graphics & Modelling·Preethi Badrinarayan, G Narahari Sastry
Feb 18, 2015·Journal of Molecular Graphics & Modelling·Rahul P GangwalAbhay T Sangamwar
Dec 2, 2011·Clinical Pharmacology and Therapeutics·J M MichalskiS I Rennard
Nov 10, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Elise BlanchardWito Richter
Aug 2, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Will McDonoughWito Richter
Aug 21, 2015·Molecular Diversity·Sara GuarientoElena Cichero
Jan 8, 2021·European Journal of Medicinal Chemistry·Nathalia Fonseca NadurArthur Eugen Kümmerle
Dec 15, 2010·Journal of Chemical Information and Modeling·Preethi Badrinarayan, G Narahari Sastry

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