scholarly journals Metabolism modifications affect drug optimization

2020 ◽  
Author(s):  
Mariah Ramos ◽  
Xinghai Chen
Keyword(s):  
Drug Optimization

scholarly journals Cryo-EM structure of the NLRP3 decamer bound to the cytokine release inhibitory drug CRID3

2021 ◽  
Author(s):  
Inga V. Hochheiser ◽  
Michael Pilsl ◽  
Gregor Hagelueken ◽  
Jonas Moecking ◽  
Michael Marleaux ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nucleotide Binding Domain ◽  
Native Form ◽  
Spherical Structure ◽  
Cryo Electron Microscopy ◽  
Rational Drug ◽  
Inhibitory Drug ◽  
Drug Optimization ◽  
Apical Axis

NLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis. The mechanisms leading to NLRP3 activation and the way how antagonistic small molecules function remain poorly understood. Here we report the cryo-electron microscopy structures of full-length NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950). Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined LRR domains that assemble back-to-back as pentamers with the NACHT domain located at the apical axis of this spherical structure. Molecular contacts between the concave sites of two opposing LRRs are mediated by an acidic loop extending from an LRR transition segment. Binding of CRID3 significantly stabilizes the NACHT and LRR domains relative to each other, allowing structural resolution of 3.9-4.2 Ang. CRID3 binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginines from opposing sites, explaining the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this lead therapeutic, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization are within reach.

Codrug: An efficient approach for drug optimization

2010 ◽  
Vol 41 (5) ◽  
pp. 571-588 ◽  
Author(s):  
N. Das ◽  
M. Dhanawat ◽  
B. Dash ◽  
R.C. Nagarwal ◽  
S.K. Shrivastava
Keyword(s):  
Efficient Approach ◽  
Drug Optimization

On Possibility of Optimization of Bone Stress Remodeling in Knee Joint Arthroplasty

2009 ◽  
Vol 16 (4) ◽  
pp. 19-23
Author(s):  
Leonid Borisovich Reznik ◽  
M A Turushev ◽  
L B Reznik ◽  
M A Turushev
Keyword(s):  
Bone Density ◽  
Distal Femur ◽  
Main Group ◽  
Control Group ◽  
Radiographic Image ◽  
Bone Stress ◽  
Patient Groups ◽  
Total Knee ◽  
Drug Optimization ◽  
Bone Tissue Remodeling

Using standard photodensitometry bone remodeling was studied in proximal tibia and distal femur after total knee arthroplasty at terms up to 12 months. Out of 120 patients 60 patients (main group) received strontium ranelate (Bivalos) for 12 months after operation and in 60 patients (control group) drug correction was not performed. By the results of standard photodensitometry in both patient groups the density of radiographic image around the implant decreased by 22% at an average within the first 2 postoperative months and that was indicative of osteolysis activity. Later on during the period from 2 to 6 months after arthroplasty the increase of optic bone density was observed. By the end of 12 month in patients from the main group the optic bone density around the implant increased by 39.6% (to preoperative level) and by 25% in controls as compared with the level recorded in 2 months after surgery. Analysis of the total knee replacement by Lischolm scale showed that drug optimization of the processes of bone tissue remodeling enabled to shorten the terms of patients' rehabilitation and to decrease the rate of unsatisfactory results.

Mechanochemical Synthesis of Bumetanide–4-Aminobenzoic Acid Molecular Cocrystals: A Facile and Green Approach to Drug Optimization

2014 ◽  
Vol 118 (31) ◽  
pp. 9180-9190 ◽  
Author(s):  
Giovanna Bruni ◽  
Mariarosa Maietta ◽  
Vittorio Berbenni ◽  
Piercarlo Mustarelli ◽  
Chiara Ferrara ◽  
...  
Keyword(s):  
Mechanochemical Synthesis ◽  
Aminobenzoic Acid ◽  
Green Approach ◽  
Drug Optimization

Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease

2005 ◽  
Vol 33 (6) ◽  
pp. 1330-1332 ◽  
Author(s):  
I. McPhee ◽  
L.C.D. Gibson ◽  
J. Kewney ◽  
C. Darroch ◽  
P.A. Stevens ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Starting Point ◽  
International Patent ◽  
Drug Optimization ◽  
High Degree

The EPAC (exchange protein directly activated by cAMP) proteins are GEFs (guanine nucleotide-exchange factors) that activate Rap GTPases upon binding to cAMP. The involvement of these proteins in a number of diseases, neurodegenerative, inflammatory and metabolic, has started to show how they may prove to be important targets for therapeutic intervention. We first became interested in EPAC when we discovered that the expression levels of both EPAC1 and EPAC2 were altered in those regions of the brain associated with Alzheimer's disease [McPhee, Breslin, Kewney, MacKenzie, Cooreman, Gibson and Hammond (2004) International Patent number WO 2004/096199 A2]. It was known that compounds could be designed to be selective for EPAC over PKA (protein kinase A); however, these compounds were all based around the core structure of cAMP. We decided to screen a small compound library (10000 compounds) to investigate the possibility of developing a compound series outside of the cAMP structure. We subsequently developed a novel, high-throughput screen based on the displacement of [3H]cAMP from the EPAC cAMP-binding site and identified small molecule hits from the Scottish Biomedical Lead Generation Library. These compounds selectively bind to the cAMP-binding sites of EPAC1 and EPAC2 and are structurally dissimilar to cAMP. They have similar affinities for both EPAC1 and EPAC2 and have a high degree of specificity for EPAC over PKA. We believe that these compounds provide a valuable starting point for a drug optimization programme.

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