Discovery of Phosphodiesterase-4 Inhibitors: Serendipity and Rational Drug Design

2014 ◽  
Vol 67 (12) ◽  
pp. 1780 ◽  
Author(s):  
Susanne C. Feil ◽  
Jessica K. Holien ◽  
Craig J. Morton ◽  
Nancy C. Hancock ◽  
Philip E. Thompson ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Sites ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Rational Drug Design ◽  
Chronic Obstructive ◽  
Structure Based Drug Design ◽  
Obstructive Pulmonary Disease ◽  
Phosphodiesterase 4 ◽  
Wide Range

Phosphodiesterase 4 (PDE4), the primary cyclic AMP-hydrolysing enzyme in cells, is a promising drug target for a wide range of mental disorders including Alzheimer's and Huntington's diseases, schizophrenia, and depression, plus a range of inflammatory diseases including chronic obstructive pulmonary disease, asthma, and rheumatoid arthritis. However, targeting PDE4 is complicated by the fact that the enzyme is encoded by four very closely related genes, together with 20 distinct isoforms as a result of mRNA splicing, and inhibition of some of these isoforms leads to intolerable side effects in clinical trials. With almost identical active sites between the isoforms, X-ray crystallography has played a critical role in the discovery and development of safer PDE4 inhibitors. Here we describe our discovery of a novel class of highly potent PDE4 via a ‘virtuous’ cycle of structure-based drug design and serendipity.

scholarly journals The Holy Grail realized: Structure-based drug design applied to GPCRs

2014 ◽  
Vol 36 (2) ◽  
pp. 23-27
Author(s):  
Simone Weyand ◽  
Christopher G. Tate
Keyword(s):  
Drug Design ◽  
Neural Activity ◽  
Neurological Disorders ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Integral Membrane Proteins ◽  
Structure Based Drug Design ◽  
Small Molecule Drugs ◽  
Wide Range ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the cornerstone of intercellular communication throughout the human body, where they control diverse physiological functions such as blood pressure, neural activity and reproduction. GPCRs have also been implicated in the pathogenesis of cancer, inflammatory diseases, metabolic imbalances and neurological disorders, and are therefore the targets of over 30% of marketed small-molecule drugs. Integral membrane proteins such as GPCRs are challenging targets for structure determination. However, generic methodologies developed over the last decade have revolutionized the field with over 20 unique GPCR structures determined, and some co-crystallized with over ten different ligands. Structure-based drug design for GPCRs is now a reality and has the potential to accelerate the development of novel therapeutics for the treatment of a wide range of disorders and diseases.

Improving the Accuracy of Protein-Ligand Binding Affinity Prediction by Deep Learning Models: Benchmark and Model

2019 ◽  
Author(s):  
Mohammad Rezaei ◽  
Yanjun Li ◽  
Xiaolin Li ◽  
Chenglong Li
Keyword(s):  
Deep Learning ◽  
Drug Design ◽  
Binding Affinity ◽  
Benchmark Dataset ◽  
Rational Drug Design ◽  
Learning Models ◽  
Structure Based Drug Design ◽  
Binding Affinity Prediction ◽  
Affinity Prediction ◽  
Rational Drug

<b>Introduction:</b> The ability to discriminate among ligands binding to the same protein target in terms of their relative binding affinity lies at the heart of structure-based drug design. Any improvement in the accuracy and reliability of binding affinity prediction methods decreases the discrepancy between experimental and computational results.<br><b>Objectives:</b> The primary objectives were to find the most relevant features affecting binding affinity prediction, least use of manual feature engineering, and improving the reliability of binding affinity prediction using efficient deep learning models by tuning the model hyperparameters.<br><b>Methods:</b> The binding site of target proteins was represented as a grid box around their bound ligand. Both binary and distance-dependent occupancies were examined for how an atom affects its neighbor voxels in this grid. A combination of different features including ANOLEA, ligand elements, and Arpeggio atom types were used to represent the input. An efficient convolutional neural network (CNN) architecture, DeepAtom, was developed, trained and tested on the PDBbind v2016 dataset. Additionally an extended benchmark dataset was compiled to train and evaluate the models.<br><b>Results: </b>The best DeepAtom model showed an improved accuracy in the binding affinity prediction on PDBbind core subset (Pearson’s R=0.83) and is better than the recent state-of-the-art models in this field. In addition when the DeepAtom model was trained on our proposed benchmark dataset, it yields higher correlation compared to the baseline which confirms the value of our model.<br><b>Conclusions:</b> The promising results for the predicted binding affinities is expected to pave the way for embedding deep learning models in virtual screening and rational drug design fields.

scholarly journals Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jomkuan Theprungsirikul ◽  
Sladjana Skopelja-Gardner ◽  
Ashley S. Burns ◽  
Rachel M. Wierzbicki ◽  
William F. C. Rigby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Opsonic Activity ◽  
Obstructive Pulmonary Disease ◽  
Neutrophil Dysfunction ◽  
Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

Chronic respiratory failure

2020 ◽  
pp. 4282-4291
Author(s):  
Michael I. Polkey ◽  
P.M.A. Calverley
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Respiratory Failure ◽  
Neuromuscular Diseases ◽  
Interstitial Lung Diseases ◽  
Alveolar Ventilation ◽  
Chronic Respiratory Failure ◽  
Clinical State ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Wide Range

Chronic respiratory failure describes a clinical state when the arterial Po2 breathing air is less than 8.0 kPa, which may or may not be associated with hypercapnia (defined as Pco2 more than 6.0 kPa (45 mm Hg)). Four processes cause arterial hypoxaemia due to inefficient pulmonary gas exchange—ventilation–perfusion (V/Q) mismatch, hypoventilation, diffusion limitation, and true shunt, with the most important of these being V/Q mismatching. The arterial CO2 is increased by inadequate alveolar ventilation and/or V/Q abnormality. A wide range of disorders can cause chronic respiratory failure, with the commonest being chronic obstructive pulmonary disease, interstitial lung diseases, chest wall and neuromuscular diseases, and morbid obesity.

scholarly journals Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

2020 ◽  
Vol 14 ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Rational Drug Design ◽  
Comprehensive Overview ◽  
Nicotinic Acetylcholine ◽  
Structure Based Drug Design ◽  
Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

scholarly journals Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases

2020 ◽  
Vol 21 (1) ◽  
pp. 307 ◽  
Author(s):  
Sara Ottolenghi ◽  
Aida Zulueta ◽  
Anna Caretti
Keyword(s):  
High Altitude ◽  
Inflammatory Diseases ◽  
Physiological Adaptation ◽  
Adaptation To Hypoxia ◽  
Chronic Obstructive ◽  
Compensatory Response ◽  
Obstructive Pulmonary Disease ◽  
Pathological Conditions ◽  
High Altitude Pulmonary Edema ◽  
Sphingosine 1 Phosphate

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.

Allyl isothiocyanate upregulates MRP1 expression through Notch1 signaling in human bronchial epithelial cells

2020 ◽  
Vol 98 (5) ◽  
pp. 324-331
Author(s):  
Ni-ni Li ◽  
Yan Guo ◽  
Cheng-jun Jiang ◽  
Yuan-yuan Zhou ◽  
Chen-hui Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Allyl Isothiocyanate ◽  
Chronic Obstructive ◽  
Therapeutic Effects ◽  
Mobility Shift ◽  
Obstructive Pulmonary Disease ◽  
Suppression Effect ◽  
Notch1 Signaling ◽  
Mrp1 Expression

Multidrug resistance associated protein-1 (MRP1) and Notch signaling are closely related and both play a critical role in chronic obstructive pulmonary disease (COPD) establishment and progression. The aim of our work was to test whether Notch1 is involved in allyl isothiocyanate (AITC) induced MRP1 expression. We used cigarette smoke extract (CSE) to simulate the smoking microenvironment in vitro. The results demonstrated that CSE led to apoptosis as well as reduced the expression of Notch1, Hes1, and MRP1, while AITC significantly reversed this downregulation. Transfected with Notch1 siRNA downregulated MRP1 expression and activity, aggravated the suppression effect by CSE, and abolished the AITC-induced Notch1, Hes1, and MRP1 expression. Validation of the correlation between Notch1 and MRP1 was implemented by gel-shift assays (electrophoretic mobility shift assay). The result revealed an interaction between a specific promoter region of MRP1 and the intracellular domain of Notch1. In conclusion, Notch1 signaling positively regulated MRP1 in 16HBE cells and AITC induced MRP1 expression and function may be attributed to Notch1 signaling. These findings show that Notch1 and MRP1 might have a potential protective effect in the COPD process and become a new therapeutic target for COPD or other lung diseases. It also provides a theoretical basis for the therapeutic effects of AITC.

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