Virtual Screening Approach to Identifying a Novel and Tractable Series of<i>Pseudomonas aeruginosa</i>Elastase Inhibitors

Leiris, Simon; Davies, David T.; Sprynski, Nicolas; Castandet, Jérôme; Beyria, Lilha; Bodnarchuk, Michael S.; Sutton, J. Mark; Mullins, T.M.G.; Jones, Mark; Forrest, Andrew K.; Pallin, T. David; Karunakar, Paduri; Martha, S.K.; Parusharamulu, Battu; Ramula, Ramesh; Kotha, Venkatesh; Pottabathini, Narender; Srinivasu, Pavuluri; Lemonnier, Marguerite; Everett, Martin

doi:10.1021/acsmedchemlett.0c00554

Cited by 12 publications

(17 citation statements)

References 21 publications

(31 reference statements)

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“…Later, the LasB inhibition through small carboxylic acid compounds was disclosed by Leiris et al ( Figure 11 ) [ 47 ]. They initiated a virtual screening based on the structure of LasB and ligand conformation.…”

Section: Lasb Inhibitorsmentioning

confidence: 99%

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

et al. 2022

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Elastase B (LasB) is a zinc metalloprotease and a crucial virulence factor of Pseudomonas aeruginosa. As the need for new strategies to fight antimicrobial resistance (AMR) constantly rises, this protein has become a key target in the development of novel antivirulence agents. The extensive knowledge of the structure of its active site, containing two subpockets and a zinc atom, led to various structure-based medicinal chemistry programs and the optimization of several chemical classes of inhibitors. This review provides a brief reminder of the structure of the active site and a summary of the disclosed P. aeruginosa LasB inhibitors. We specifically focused on the analysis of their binding modes with a detailed representation of them, hence giving an overview of the strategies aiming at targeting LasB by small molecules.

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Section: Lasb Inhibitorsmentioning

confidence: 99%

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

et al. 2022

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“…[ 19 , 23 ] It has the ability to degrade elastin, an important component of lung tissue, blood vessels and skin, which makes it a key target for inhibition. Until now, natural products such as the streptomyces metalloprotease inhibitor (SMPI) from Streptomyces nigrescens TK‐23 [24] and phosphoramidon (Pam) [25] (Figure 1 , compound 1 ), small peptides containing metal‐chelating motifs such as thiol,[ 26 , 27 , 28 ] hydroxamate [29] or carboxylic acid[ 30 , 31 ] groups (Figure 1 , compound 2 ), have been reported. However, most of these inhibitors show poor selectivity with respect to mammalian metalloenzymes.…”

mentioning

confidence: 99%

Substrate‐Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors

et al. 2021

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Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a submicromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.Alternative binding modes are often observed in the realm of fragment-based drug design. [1] Despite the potential to significantly accelerate hit-to-lead optimization, there are few examples of successful fragment linking/merging or systematic exploitation of such invaluable sources of structural information. This is presumably due to a number of conditions that need to be met such as the linker composition and the resulting ADMET properties. [2,3] We [

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“…Meanwhile, the following proteins were used for K. pneumoniae infection: KPC-2 carbapenemase (PDB ID: 2OV5) and CTX-M-15 enzyme (PDB ID: 4S2I; chain A). These enzymes are commonly targeted in silico for drug development due to their involvement in infectivity and/or multi-drug resistance mechanisms of the bacteria [49][50][51][52][53][54][55].…”

Section: Molecular Dockingmentioning

confidence: 99%

Antibacterial and COX-2 Inhibitory Tetrahydrobisbenzylisoquinoline Alkaloids from the Philippine Medicinal Plant Phaeanthus ophthalmicus

Magpantay

Malaluan

Manzano

et al. 2021

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Phaeanthus ophthalmicus (Roxb. ex G.Don) J.Sinclair (previously known as P. ebracteolatus (Presl) Merr) is a Philippine medicinal plant occurring as evergreen shrub in the lowland forests of Luzon islands. It is used traditionally by Filipinos to treat bacterial conjunctivitis, ulcer and wound infections. Based on previous investigations where cyclooxygenase-2 (COX-2) functions as immune-linked factor in infectious sensitivities to bacterial pathogens by triggering pro-inflammatory immune-associated reactions, we investigated the antimicrobial and COX inhibitory activities of the extracts and tetrahydrobisbenzylisoquinoline alkaloids of P. ophthalmicus in vitro and in silico to validate its ethnomedicinal uses. Thus, the dichloromethane–methanol (DCM–MeOH) crude extract and alkaloid extracts exhibiting antibacterial activities against drug-resistant bacterial strains such as methicillin-resistance Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Klebsiella pneumoniae + CRE and Pseudomonas aeruginosa + MBL afforded (+)-tetrandrine (1) and (+)-limacusine (2) as the major biologically active tetrahydrobisbenzylisoquinoline alkaloidal constituents after purification. Both tetrahydrobisbenzylisoquinoline alkaloids 1 and 2 showed broad spectrum antibacterial activity with strongest inhibition against the Gram-negative bacteria MβL-Pseudomonas aeruginosa Klebsiella pneumoniae + CRE. Interestingly, the alkaloid limacusine (2) showed selective inhibition against ovine COX-2 in vitro. These results were ascertained by molecular docking and molecular dynamics simulation experiments where alkaloid 2 showed strong affinity in the catalytic sites of Gram-negative bacterial enzymes P. aeruginosa elastase and K. pneumoniae KPC-2 carbapenemase (enzymes involved in infectivity mechanisms), and of ovine COX-2. Overall, our study provides credence on the ethnomedicinal use of the Philippine medicinal plant P. ophthalmicus as traditional plant-based adjuvant to treat bacterial conjunctivitis and other related infections. The antibacterial activities and selective COX-2 inhibition observed for limacusine (2) point to its role as the biologically active constituent of P. ophthalmicus. A limited number of drugs with COX-2 inhibitory properties like celecoxib also confer antibacterial activity. Thus, tetrahydrobisbenzyl alkaloids, especially 2, are promising pharmaceutical inspirations for developing treatments of bacterial/inflammation-related infections.

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Virtual Screening Approach to Identifying a Novel and Tractable Series ofPseudomonas aeruginosaElastase Inhibitors

Cited by 12 publications

References 21 publications

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

Substrate‐Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors

Antibacterial and COX-2 Inhibitory Tetrahydrobisbenzylisoquinoline Alkaloids from the Philippine Medicinal Plant Phaeanthus ophthalmicus

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