New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding

Abstract

Abstract:Bradykinin (BK) is a member of the kinin family, released in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases, provoking vasodilatation and increased vascular permeability among other effects. Their actions are mediated through at least two G-protein coupled receptors, B1 a receptor upregulated during inflammation episodes or tissue trauma and B2 that is constitutively expressed in a variety of cell types. The goal of the present work is to carry out a structure-activity study of BK B2 antagonism, taking into account the stereochemical features of diverse non-peptide antagonists and the way these features translate into ligand anchoring points to complementary regions of the receptor, through the analysis of the respective ligand-receptor complex. For this purpose an atomistic model of the BK B2 receptor was built by homology modeling and subsequently refined embedded in a lipid bilayer by means of a 600 ns molecular dynamics trajectory. The average structure from the last hundred nanoseconds of the molecular dynamics trajectory was energy minimized and used as model of the receptor for docking studies. For this purpose, a set of compounds with antagonistic profile, covering maximal diversity were selected from the literature. Specifically, the set of compounds include Fasitibant, FR173657, Anatibant, WIN64338, Bradyzide, CHEMBL442294, and JSM10292. Molecules were docked into the BK B2 receptor model and the corresponding complexes analyzed to understand ligand-receptor interactions. The outcome of this study is summarized in a 3D pharmacophore that explains the observed structureactivity results and provides insight into the design of novel molecules with antagonistic profile. To prove the validity of the pharmacophore hypothesized a virtual screening process was also carried out. The pharmacophore was used as query to identify new hits using diverse databases of molecules. The results of this study revealed a set of new hits with structures not connected to the molecules used for pharmacophore development. A few of these structures were purchased and tested. The results of the binding studies show about a 33% success rate with a correlation between the number of pharmacophore points fulfilled and their antagonistic potency. Some of these Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationstructures are disclosed in the present work.Response to Reviewers: We sincerely appreciate the involvement of reviewer #1 and are deeply obliged. The reviewer was right in pointing the distortion of the ring and the amide in Figure 8 that has now been fixed in the revised version of Figure 8. We have also modified the viewpoint of Figure 9 to clearly show the protonation status of the terminal amine that was unfortunately hidden in the previous version of Figure 9 this study is summarized in a 3D pharmacophore that explains the observed structure-activity results and provides insight into the design of novel molecules with antagonistic profile. ...

Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects

“…Docking results confirmed that the two compounds share the same region of the binding site, highlighting the importance of specific anchor points that were previously reported to be necessary for allosteric inhibition by our group [ 19 ] and specifically reported for B1 receptor inhibition in a recent paper [ 23 ]. Docking simulation highlighted how the compound DFL20656 interacts with N114 3.29 and W93 2.60 ( Figure 2 ).…”

“…To overcome the bias of the templates used in the generation of the model, MD simulation was run allowing the homology model to equilibrate long enough to likely adopt what is more likely a biologically relevant structure [ 43 ]. To evaluate the structural stability of the protein-membrane system, 200 ns of molecular dynamics simulation were run [ 23 , 44 ].…”

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

“…Novel approaches promise to facilitate the design of original kinin receptor ligands in the future, such as the in silico definition of pharmacophores from the analysis of the docking of several non-peptide antagonists; this has been done for 3-dimensional models of both the B 1 R and B 2 R [90,91]. The pro-drug agonist peptides may be further optimized for additional peptidases that will provide targeted actions on a specific tissue of a selective physiological function.…”

The role of contact system in septic shock: the next target? An overview of the current evidence

“…They built an atomistic model of the receptor aiming to provide deeper insight into its structure, and their experiment allowed to define a common pharmacophore. This finding is potentially useful for the discovery of new compounds [22]. …”