scholarly journals Molecular basis of agonist docking in a human GPR103 homology model by site-directed mutagenesis and structure-activity relationship studies

2014 ◽  
Vol 171 (19) ◽  
pp. 4425-4439 ◽  
Author(s):  
C Neveu ◽  
F Dulin ◽  
B Lefranc ◽  
L Galas ◽  
C Calbrix ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Homology Model ◽  
Structure Activity Relationship ◽  
Site Directed Mutagenesis ◽  
Activity Relationship ◽  
Directed Mutagenesis ◽  
Structure Activity

Probing the structure-activity relationship of Escherichia coli LT-A by site-directed mutagenesis

1994 ◽  
Vol 14 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Mariagrazia Pizza ◽  
Mario Domenighini ◽  
Wim Hol ◽  
Valentine Giannelli ◽  
Maria Rita Fontana ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Structure Activity Relationship ◽  
Site Directed Mutagenesis ◽  
Activity Relationship ◽  
Directed Mutagenesis ◽  
Structure Activity ◽  
Relationship Of

scholarly journals In SilicoScreening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis

2010 ◽  
Vol 55 (2) ◽  
pp. 659-666 ◽  
Author(s):  
Jaspreet Kaur ◽  
Pranav Kumar ◽  
Sargam Tyagi ◽  
Richa Pathak ◽  
Sanjay Batra ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Enzyme Inhibition ◽  
Homology Model ◽  
Structure Activity Relationship ◽  
Recombinant Enzyme ◽  
Rational Drug Design ◽  
Activity Relationship ◽  
Inhibition Assay ◽  
Structure Activity ◽  
Enzyme Inhibition Assay

ABSTRACTIn this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) inLeishmaniaparasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site ofLeishmania donovaniPTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfectedL. donovanipromastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture. Flow cytometry results indicated that 7-(4-chlorobenzyl)-3-methyl-4-(4-trifluoromethyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (compound 7) was 10 times more active onL. donovaniamastigotes (50% inhibitory concentration [IC50] = 3 μM) than on promastigotes (IC50= 29 μM). Compound 7 exhibited aKivalue of 0.72 μM in a recombinant enzyme inhibition assay. We discovered that novel pyrimido[1,2-a]pyrimidin-2-one systems generated from the allyl amines afforded from the Baylis-Hillman acetates could have potential as a valuable pharmacological tool against the neglected disease visceral leishmaniasis.

scholarly journals Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Benzopyran-Based Inhibitors

2021 ◽  
Vol 8 ◽  
Author(s):  
Sudarsana Reddy Vanga ◽  
Johan Åqvist ◽  
Anders Hallberg ◽  
Hugo Gutiérrez-de-Terán
Keyword(s):  
Binding Affinity ◽  
Binding Mode ◽  
Structure Activity Relationship ◽  
Site Directed Mutagenesis ◽  
Activity Relationship ◽  
Structural Basis ◽  
Binding Model ◽  
Linear Interaction ◽  
Structure Activity ◽  
Energy Perturbation

Inhibition of the insulin-regulated aminopeptidase (IRAP) improves memory and cognition in animal models. The enzyme has recently been crystallized and several series of inhibitors reported. We herein focused on one series of benzopyran-based inhibitors of IRAP known as the HFI series, with unresolved binding mode to IRAP, and developed a robust computational model to explain the structure-activity relationship (SAR) and potentially guide their further optimization. The binding model here proposed places the benzopyran ring in the catalytic binding site, coordinating the Zn2+ ion through the oxygen in position 3, in contrast to previous hypothesis. The whole series of HFI compounds was then systematically simulated, starting from this binding mode, using molecular dynamics and binding affinity estimated with the linear interaction energy (LIE) method. The agreement with experimental affinities supports the binding mode proposed, which was further challenged by rigorous free energy perturbation (FEP) calculations. Here, we found excellent correlation between experimental and calculated binding affinity differences, both between selected compound pairs and also for recently reported experimental data concerning the site directed mutagenesis of residue Phe544. The computationally derived structure-activity relationship of the HFI series and the understanding of the involvement of Phe544 in the binding of this scaffold provide valuable information for further lead optimization of novel IRAP inhibitors.

Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis

Planta Medica ◽  
2008 ◽  
Vol 74 (09) ◽  
Author(s):  
MA Brenzan ◽  
CV Nakamura ◽  
BPD Filho ◽  
T Ueda-Nakamura ◽  
MCM Young ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Leishmania Amazonensis ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Of
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