Structure-Based Drug Design of a Novel Family of PPARγ Partial Agonists:  Virtual Screening, X-ray Crystallography, and in Vitro/in Vivo Biological Activities

2006 ◽  
Vol 49 (9) ◽  
pp. 2703-2712 ◽  
Author(s):  
I-Lin Lu ◽  
Chien-Fu Huang ◽  
Yi-Hui Peng ◽  
Ying-Ting Lin ◽  
Hsing-Pang Hsieh ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Biological Activities ◽  
Structure Based Drug Design ◽  
X Ray ◽  
X Ray Crystallography ◽  
Partial Agonists

scholarly journals The critical role of QM/MM X-ray refinement and accurate tautomer/protomer determination in structure-based drug design

2020 ◽  
Author(s):  
Oleg Y. Borbulevych ◽  
Roger I. Martin ◽  
Lance M. Westerhoff
Keyword(s):  
Drug Design ◽  
Critical Role ◽  
Pharmaceutical Research ◽  
Energy Functional ◽  
Structural Refinement ◽  
Structure Based Drug Design ◽  
X Ray ◽  
X Ray Crystallography ◽  
Refinement Method ◽  
The Impact

Abstract Conventional protein:ligand crystallographic refinement uses stereochemistry restraints coupled with a rudimentary energy functional to ensure the correct geometry of the model of the macromolecule—along with any bound ligand(s)—within the context of the experimental, X-ray density. These methods generally lack explicit terms for electrostatics, polarization, dispersion, hydrogen bonds, and other key interactions, and instead they use pre-determined parameters (e.g. bond lengths, angles, and torsions) to drive structural refinement. In order to address this deficiency and obtain a more complete and ultimately more accurate structure, we have developed an automated approach for macromolecular refinement based on a two layer, QM/MM (ONIOM) scheme as implemented within our DivCon Discovery Suite and "plugged in" to two mainstream crystallographic packages: PHENIX and BUSTER. This implementation is able to use one or more region layer(s), which is(are) characterized using linear-scaling, semi-empirical quantum mechanics, followed by a system layer which includes the balance of the model and which is described using a molecular mechanics functional. In this work, we applied our Phenix/DivCon refinement method—coupled with our XModeScore method for experimental tautomer/protomer state determination—to the characterization of structure sets relevant to structure-based drug design (SBDD). We then use these newly refined structures to show the impact of QM/MM X-ray refined structure on our understanding of function by exploring the influence of these improved structures on protein:ligand binding affinity prediction (and we likewise show how we use post-refinement scoring outliers to inform subsequent X-ray crystallographic efforts). Through this endeavor, we demonstrate a computational chemistry ↔ structural biology (X-ray crystallography) "feedback loop" which has utility in industrial and academic pharmaceutical research as well as other allied fields.

scholarly journals Synthesis, characterization, biological activities, and catalytic applications of alcoholic extract of saffron (Crocus sativus) flower stigma-based gold nanoparticles

2021 ◽  
Vol 10 (1) ◽  
pp. 230-245
Author(s):  
Fahad A. Alhumaydhi ◽  
Ibrahim Khan ◽  
Abdur Rauf ◽  
Muhammad Nasimullah Qureshi ◽  
Abdullah S. M. Aljohani ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Biological Activities ◽  
Inhibitory Effect ◽  
Biological Properties ◽  
Crocus Sativus ◽  
Alcoholic Extract ◽  
X Ray ◽  
Vis Spectroscopy

Abstract Currently, nanotechnology is gaining massive attention compared to conventional methods as the biosynthesis of plant-based nanoparticles is considered safe, effective, and ecofriendly. Therefore, keeping in view the importance of nanotechnology, the present study was designed to synthesize, characterize, and evaluate the biological effectiveness of saffron stigma-based gold nanoparticles (SS-AuNPs) for their in vitro and in vivo biological properties. These gold nanoparticles were characterized by UV–Vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD). The highest antibacterial effect was observed by the saffron extract against Escherichia coli (22 mm). SS-AuNPs significantly inhibited the activity of enzyme urease (54.98%) and CA-II (64.29%). However, the nonsignificant inhibitory effect was observed in the case of α-chymotrypsin. Maximum analgesic (84.98%) and antiinflammatory (88.98%) effects were observed for SS-AuNPs (10 mg/kg). Similarly, SS-AuNPs demonstrated a significant (P < 0.01) sedative effect at all tested doses.

scholarly journals Structural changes of TasA in biofilm formation ofBacillus subtilis

2018 ◽  
Vol 115 (13) ◽  
pp. 3237-3242 ◽  
Author(s):  
Anne Diehl ◽  
Yvette Roske ◽  
Linda Ball ◽  
Anup Chowdhury ◽  
Matthias Hiller ◽  
...  
Keyword(s):  
Structural Change ◽  
Structural Changes ◽  
Analytical Ultracentrifugation ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
X Ray ◽  
X Ray Crystallography ◽  
Angle Spinning

Microorganisms form surface-attached communities, termed biofilms, which can serve as protection against host immune reactions or antibiotics.Bacillus subtilisbiofilms contain TasA as major proteinaceous component in addition to exopolysaccharides. In stark contrast to the initially unfolded biofilm proteins of other bacteria, TasA is a soluble, stably folded monomer, whose structure we have determined by X-ray crystallography. Subsequently, we characterized in vitro different oligomeric forms of TasA by NMR, EM, X-ray diffraction, and analytical ultracentrifugation (AUC) experiments. However, by magic-angle spinning (MAS) NMR on live biofilms, a swift structural change toward only one of these forms, consisting of homogeneous and protease-resistant, β-sheet–rich fibrils, was observed in vivo. Thereby, we characterize a structural change from a globular state to a fibrillar form in a functional prokaryotic system on the molecular level.

Carbamoyl Imidazoles As Potent, Reversible and Competitive Cruzain Inhibitors with in vitro and in vivo Trypanocidal Activity: A Structure-Based Drug Design Approach

2019 ◽  
Author(s):  
Mariana L. de Souza ◽  
Celso de Oliveira Rezende Junior ◽  
Rafaela S. Ferreira ◽  
Rocio Marisol Espinoza Chávez ◽  
Leonardo Ferreira ◽  
...  
Keyword(s):  
Drug Design ◽  
Design Approach ◽  
Structure Based Drug Design ◽  
Trypanocidal Activity ◽  
Cruzain Inhibitors
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