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

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.

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Medicinal Chemistry and Molecular Modeling: An Integration To Teach Drug Structure–Activity Relationship and the Molecular Basis of Drug Action

Journal of Chemical Education ◽

10.1021/ed082p588 ◽

2005 ◽

Vol 82 (4) ◽

pp. 588 ◽

Cited By ~ 25

Author(s):

Ivone Carvalho ◽

Áurea D.L. Borges ◽

Lílian S.C. Bernardes

Keyword(s):

Molecular Modeling ◽

Molecular Basis ◽

Medicinal Chemistry ◽

Structure Activity Relationship ◽

Drug Action ◽

Activity Relationship ◽

Structure Activity

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

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.625274 ◽

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.

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