The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold

Dziadulewicz, Edward K.; Brown, Michael C.; Dunstan, Andrew; Lee, Wai; Said, Najeeb B.; Garratt, Peter J.

doi:10.1016/s0960-894x(99)00015-3

Cited by 61 publications

(30 citation statements)

References 18 publications

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“…This compound (6, in Figure 1) was the most active compound of a series of benzodiazepines designed to mimic the β-turn adopted by BK in its bioactive form [25]. This peptidomimetic exhibits a binding affinity for the BK B2 receptor in the micromolar range, result that is consistent with the low affinity exhibited by a series of cyclic peptides designed to mimic the C-terminus of BK [13,14].…”

Section: Chembl442294mentioning

confidence: 63%

“…Aimed at finding compounds with lower molecular mass, scientists at Jerini carried out a medicinal chemistry optimization process, using the 8-benzyloxy-2-methyl-quinoline moiety, that is the common scaffold of several of the nonpeptide antagonists listed above, as starting structure. Their study led to the design and synthesis of JSM10292 a potent B2 antagonist with similar affinity and selectivity to the previous compounds, but with lower molecular mass [25].…”

Section: Introductionmentioning

confidence: 99%

“…For this purpose we selected a set of compounds from the literature covering maximal diversity. The compounds selected for the present study include Fasitibant (1) [24], FR173657 (2) [21], Anatibant (3) [23], WIN64338 (4) [20], Bradyzide (5) [22], CHEMBL442294 (6) [25], and JSM10292 (7) [26], shown in Figure 1. Compounds were docked into a refined model of the BK B2 receptor constructed by homology modeling, following the procedure explained in the methods section, and the complexes were further analyzed for their ligand-receptor interactions.…”

Section: Introductionmentioning

confidence: 99%

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

Lupala

Gómez-Gutiérrez

Pérez

2016

Journal of Molecular Graphics and Modelling

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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. ...

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Section: Chembl442294mentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lupala

Gómez-Gutiérrez

Pérez

2016

Journal of Molecular Graphics and Modelling

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“…An example of such strategy is that of Zappalà's team [92,93]. These authors synthesized a series of Cys protease inhibitors based on the 1,4-benzodiazepine scaffold, which is known to act as a good mimetic of -turns [113], the structural motif postulated as the biological active form of the D-Ser-Gly peptide [114]. Furthermore, benzodiazepines are also known to enhance oral bioavailabilitity and also to increase stability toward premature proteolytic degradation by enzymes.…”

Section: Irreversible Inhibitorsmentioning

confidence: 99%

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

Pérez

Teixeira

Gomes³

et al. 2013

CMC

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New drug targets for the development of antimalarial drugs have emerged after the unveiling of the Plasmodium falciparum genome in 2002. Potential antimalarial drug targets can be broadly classified into three categories according to their function in the parasite's life cycle: (i) biosynthesis, (ii) membrane transport and signaling, and (iii) hemoglobin catabolism. The latter plays a key role, as inhibition of hemoglobin degradation impairs maturation of bloodstage malaria parasites, ultimately leading to remission or even cure of the most severe stage of the infection. Intraerythrocytic Plasmodia parasites have limited capacity to biosynthesize amino acids which are vital for their growth. Therefore, the parasites obtain those essential amino acids via degradation of host cell hemoglobin, making this a crucial process for parasite survival. Several plasmodial proteases are involved in hemoglobin catabolism, among which plasmepsins and falcipains are well-known examples. Hence, development of P. falciparum protease inhibitors is a promising approach to antimalarial chemotherapy, as highlighted by the present review which is focused on the Medicinal Chemistry research effort recorded in the past decade in this particular field.

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“…Using radicals with different chemical and physical properties to obtain derivates of basis molecules we created some compounds with affinity for specific biological targets [11]. These substances can mimic the βbend that is important for their biochemical activity [5]. In addition, such compounds are well sustained by patients.…”

mentioning

confidence: 99%

Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction

Virych¹,

Shelyuk²,

Kabanova³

2017

Ukr.Biochem.J.

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The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold

Cited by 61 publications

References 18 publications

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

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

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction

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