Structure based virtual screening for discovery of novel human neutrophil elastase inhibitors

Lucas, Susana D.; Gonçalves, Lídia; Cardote, Teresa A.F.; Correia, Henrique F.; Moreira, Rui; Guedes, Rita C.

doi:10.1039/c2md20090b

Cited by 15 publications

(14 citation statements)

References 24 publications

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“…Melting points (m.p.) were determined using a Bock-Monoscop (Kofler, Berlin, Germany Fluorometric assays for HNE inhibition activity were conducted as previously described [37]. Briefly, the assays were carried out in 200 µL assay buffer (0.1 M HEPES pH 7.…”

Section: Synthesis and Characterization Of Hne Inhibitorsmentioning

confidence: 99%

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Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

et al. 2020

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Human neutrophil elastase (HNE) is a serine protease that degrades matrix proteins. An excess of HNE may trigger several pathological conditions, such as psoriasis. In this work, we aimed to synthesize, characterize and formulate new HNE inhibitors with a 4-oxo-β-lactam scaffold with less toxicity, as well as therapeutic index in a psoriasis context. HNE inhibitors with 4-oxo-β-lactam scaffolds were synthesized and characterized by NMR, FTIR, melting point, mass spectrometry and elemental analysis. In vitro cytotoxicity and serine protease assays were performed. The compound with the highest cell viability (AAN-16) was selected to be incorporated in an emulsion (AAN-16 E) and in a microemulsion (AAN-16 ME). Formulations were characterized in terms of organoleptic properties, pH, rheology, droplet size distribution, in vitro drug release and in vivo psoriatic activity. All compounds were successfully synthesized according to analytical methodology, with good yields. Both formulations presented suitable physicochemical properties. AAN-16 E presented the most promising therapeutic effects in a murine model of psoriasis. Overall, new HNE inhibitors were synthesized with high and selective activity and incorporated into topical emulsions with potential to treat psoriasis.

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Section: Synthesis and Characterization Of Hne Inhibitorsmentioning

confidence: 99%

“…For all serine proteases, the activity was measured at excitation and emission wavelengths of 360 nm and 460 nm, respectively, in a microplate reader (FLUOstar Omega, BMG Labtech, Germany). The IC 50 was determined by non-linear regression as previously published [37].…”

Section: Synthesis and Characterization Of Hne Inhibitorsmentioning

confidence: 99%

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

et al. 2020

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“…Several studies have been conducted recently to examine the binding interaction of inhibitors to the human neutrophil elastase structure (Siedle et al, 2002;Sivamani et al, 2012;Lucas et al, 2013;Crocetti et al, 2013;Radhakrishnan et al, 2013). In the present study, the aim is to understand the binding interactions between curcumin analogues and the active site of the human neutrophil elastase.…”

Section: Resultsmentioning

confidence: 99%

Molecular docking analysis of curcumin analogues as human neutrophil elastase inhibitors

Narayanaswamy¹,

Lam²,

Abas³

et al. 2014

Bangladesh J Pharmacol

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In the present study, we aimed to dock 17 different ligands of curcumin analogues with that of human neutrophil elastase. Molecular descriptors analysis using Molinspiration online tool was carried out including investigation on human neutrophil elastase putative binding sites using Discovery Studio. The molecular physicochemical analysis revealed that all of the curcumin analogues complied well with the five rules of thumb. With regard to bioactivity score, compound 17 has exhibited least score towards nuclear receptor ligand (0.05) and enzyme inhibitor (0.10) compared to all other ligands. Compounds 2, 4 and 13 exhibited the maximum interaction energy (-40 kcal/ mol). Interestingly, seven compounds namely 3, 11-14, 16 and 17 interacted well with Arg147 amino acid residue. The present study outcomes therefore might provide new insight in understanding these 17 curcumin analogues as potential candidates for human neutrophil elastase inhibitory agents. Article Info

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“…5 Our group has been engaged in the development of HNE inhibitors with new architectures such as the potent oxo-βlactam class, 6 or kojic acid derived inhibitors identified by a computer-aided campaign. 7,8 Exploitation of the reactivity of covalent inhibitors also allowed us to design a selective fluorescence activity-based probe as a tool for molecular functional analysis of HNE-related disease proteomes. 9 Following our journey pursuing new lead structures for HNE inhibition, we envisaged aurone derivatives as potential C-shape candidates toward suitable conformation for non-covalent HNE inhibition (Fig.…”

mentioning

confidence: 99%

“…Progress curve analysis shows concentration-dependent but not time-dependent inhibition, in line with a competitive mechanism. 7,19,20 In order to have a molecular insight into the mode of action of aurone HNE inhibitors, molecular docking studies were performed using GOLD version 5.2.0 software and HNE 3D coordinates from PDB ID 3Q77, where HNE forms a complex which exhibited the ability of a non-covalent dihydropyrimidone inhibitor to adopt induced-fit C-shape inactivation of the enzyme. 4,21 The docked poses of the active aurones clearly show the ability of these derivatives (10,12,14,17,20 and 25, Fig.…”

mentioning

confidence: 99%

Discovery of C-shaped aurone human neutrophil elastase inhibitors

et al. 2015

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Structure based virtual screening for discovery of novel human neutrophil elastase inhibitors

Cited by 15 publications

References 24 publications

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

Molecular docking analysis of curcumin analogues as human neutrophil elastase inhibitors

Discovery of C-shaped aurone human neutrophil elastase inhibitors

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