Combined ligand based pharmacophore modeling, virtual screening methods to identify critical chemical features of novel potential inhibitors for phosphodiesterase-5 (original) (raw)
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Biochemical and Biophysical Research Communications, 2000
We have identified and characterised a novel member of the PDE7 family of cyclic nucleotide phosphodiesterases (PDE), which we have designated PDE7B. Mouse and human full-length cDNAs were isolated encoding a protein of 446 and 450 amino acids, respectively. The predicted protein sequence of PDE7B showed highest homology (70% identity) to that of PDE7A. Northern blot analysis identified a single 5.5-kb transcript with highest levels detected in brain, heart, and liver. Kinetic analysis of the mouse and human purified recombinant enzymes show them to specifically hydrolyse cAMP with a K m of 0.1 and 0.2 M respectively. Inhibitor studies show sensitivity to dipyridamole, IC 50 of 0.51 and 1.94 M, and IBMX, IC 50 of 3.81 and 7.37 M, for the mouse and human enzymes, respectively. This shows that dipyridamole is not selective for cGMP over cAMP PDEs as previously believed. Other standard PDE inhibitors including zaprinast, rolipram, and milrinone do not significantly inhibit PDE7B.
Classification of Phosphodiesterases and the Therapeutic Effects of their Inhibitors (Review
—Phosphodiesterase (PDE) is an enzyme that catalyses the hydrolysis of phosphodiester bonds. The enzyme is also takes responsibility for the hydrolysis of cyclic 3',5'adenosine monophosphate (cAMP) and 3',5'cyclic guanosine monophosphate (cGMP). The PDE enzymes in mammals are classified into 11 families, namely PDE1-PDE11. The classification is on the basis of amino acid sequences, substrate specificities, regulatory properties, pharmacological properties, tissue distribution. Various PDE of the same family are related with regards to functionality but differs in their specificities for substrates. Some are hydrolases with selective preferences for cAMP (PDE4, 7 and 8), while the selective preference for some others is for cGMP (PDE5, 6 and 9). Some have the ability to hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11). cAMP, and cGMP both has important roles in the regulation of inotropic mechanisms in the human myocardium. However, cAMP greatly affects other tissues, and different phosphodiesterase isoenzymes are found in many other tissues. Drugs with inhibitory effects on phosphodiesterase (thus reducing the breakdown of cAMP) have a therapeutic action on the heart, lung, and vasculature as well as on platelet function and inflammatory mechanisms. Inhibitors like these are commonly used as "biochemical tools" to study of role which cyclic nucleotides plays in the cell, but they also may be useful to investigate the structural and functional activities of PDE. As therapeutic agents, they can also be utilized in controlling the pathophysiological changes of responses generated by the cyclic nucleotides in the central nervous system (CNS), cardio-vascular, lung, digestive tract and respectively. PDE enzymes are often targets for inhibition by pharmacological processes due to their unique tissue distribution, structural and functional properties and the inflammatory process. The effect of many of these drugs is evident in more than one isoenzyme, and many tissues possess more than one isoenzyme. As a result, phosphodiesterase inhibitors (PDEI) can have a multiplicity of effects. For example, theophylline has effects on the lung, as well as cardiac and vascular effects; amrinone affects cardiac, vascular and platelet functions. The PDE inhibition, change the intracellular response to extra cellular signals by affecting the processes by the the cyclic nucleotides.
Pharmacological potential of PDE5 inhibitors for the treatment of Cystic Fibrosis
Cystic Fibrosis-Renewed Hopes Through Research 414 in clinical use for the treatment of erectile dysfunction and/or of pulmonary arterial hypertension, rescue F508del-CFTR trafficking [7,8] and improve its channel activity [9,10]. PDE are enzymes that regulate the intracellular levels of the second messengers, such as cyclic AMP and GMP, by controlling their rate of degradation. The enzymes catalyze the hydrolysis of the 3' cyclic phosphate bonds of adenosine (Figure 1) and/or guanosine 3'5' cyclic monophosphate. Fig. 1. Structure of cyclic AMP. Arrow indicates the site of hydrolyses by phosphodiesterases: the 3' cyclic phosphate bond. Many of the early studies on cyclic nucleotides were directed toward understanding PDE activity since at that time it was much easier to measure PDE activity than either cAMP or cGMP themselves or the enzymes that catalyzed their synthesis. More recently, it became clear that there were likely to be multiple isoforms of PDEs with different kinetic and regulatory properties. They are characterized by their specificity and sensitivity to calciumcalmodulin and by their affinity for cAMP or cGMP [11]. PDEs were classified on the basis of their amino acid sequences, substrate specificities, pharmacological properties and tissue distributions. 2. Cyclic nucleotide phosphodiesterases 2.1 Isoforms of phosphodiesterases It is now very clear that any single cell type can express several different PDE isoforms and also that the nature and localization of these PDEs are likely to be major regulators of the local concentrations of cAMP or cGMP in the cell. Eleven cyclic PDE families with varying selectivities for cAMP and/or cGMP have been identified in mammalian tissues [12-16] (Table 1). PDEs are therefore important regulators of diverse biochemical mechanisms mediated by cAMP and /or cGMP. Despite this heterogeneity, there is a surprising degree of homology within their catalytic domains; however, slight structural differences in these domains determine whether a PDE is cAMP
Biochemical Journal, 2003
cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMPspecific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins Abbreviations used : AKAP, A-kinase anchoring protein ; β 2 -AR, β 2 -adrenoceptor ; cAMP-GEFs, cAMP-activated GTP-exchange factors ; COPD, chronic obstructive pulmonary disease ; D440N (etc.) mutation, Asp 440 Asn (etc.) ; ERK, extracellular-signal-related protein kinase ; FYVE, a domain named after the first letter of the first four proteins in which it was found (Fab1p, YOTB, Vac1p and EEA1) ; GPCR, G-protein-coupled receptor ; GPK, G-protein-receptor kinase ; IL, interleukin ; JNK, c-Jun N-terminal kinase ; LR1 and LR2, linker regions 1 and 2 ; Lyn, an Src family protein-tyrosine kinase ; mAKAP, muscle-selective AKAP ; PA, phosphatidic acid ; PDB, Protein Data Bank ; PDE, phosphodiesterase ; PGE 2 , prostaglandin E 2 ; PKA, cAMPdependent protein kinase ; PS, phosphatidylserine ; RACK1, receptor for activated C kinase 1 ; RAID1, RACK1 interaction domain ; Rap1, a small GTPase ; RASM, rat aortic smooth muscle ; SH3, Src-homology 3 ; UCR, upstream conserved region ; WD repeat, tryptophan/aspartate repeat ; when referring to the Figures, the one-letter amino acid code is used.
Medicinal Research Reviews, 2005
The activity of phosphodiesterases (PDEs) is associated with a wide variety of diseases and an intense effort toward the development of specific PDEs inhibitors has been generated for the last years. They are the enzymes responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate, and their complexity, as well as their different functional role, makes these enzymes a very attractive therapeutic target. This review is focused on the role of PDEs played on immunomodulatory processes and the advance on the development of specific inhibitors, covering PDEs mainly related to the regulation of autoimmune processes, PDE4 and PDE7. The review also highlights the novel structural classes of PDE4 and PDE7 inhibitors, and the therapeutic potential that combined PDE4/PDE7 inhibitors offer as immunomodulatory agents. ß