Molecular insight into pseudolysin inhibition using the MM-PBSA and LIE methods

Adekoya, Olayiwola A.; Willassen, Nils Peder; Sylte, Ingebrigt

doi:10.1016/j.jsb.2005.11.003

Cited by 22 publications

(19 citation statements)

References 66 publications

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“…Specific inhibitors directing PЈ 1 Phe dipeptide templates against LasB have been employed successfully in rabbit models of corneal keratitis (1,4,22,25,53). Phosphoramidon has also been investigated for its protective effect in corneal ulcer caused by P. aeruginosa (22).…”

Section: Resultsmentioning

confidence: 99%

Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

Cathcart

Quinn

Greer³

et al. 2011

Antimicrob Agents Chemother

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Pseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial biofilm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed "second-generation" antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB, N-mercaptoacetyl-Phe-Tyr-amide (K i ‫؍‬ 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in biofilm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal biofilms, and to eradicate biofilm completely when used in combination with conventional antibiotics.

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Section: Resultsmentioning

confidence: 99%

Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

Cathcart

Quinn

Greer³

et al. 2011

Antimicrob Agents Chemother

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“…From modeling studies and molecular dynamics simulation of the complex formation it is apparent that the ridged active site loop of SMPI is complementary in shape and surface charge distribution to the active site cleft of thermolysin [72]. The complex stability is further enforced by contact sites outside the loop [73; 74]. …”

Section: - Characterization Of Prokaryote-derived Protein Inhibitmentioning

confidence: 99%

Prokaryote-derived protein inhibitors of peptidases: A sketchy occurrence and mostly unknown function

Kantyka¹,

Rawlings²,

Potempa³

2010

Biochimie

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In metazoan organisms protein inhibitors of peptidases are important factors essential for regulation of proteolytic activity. In vertebrates genes encoding peptidase inhibitors constitute up to 1% of genes reflecting a need for tight and specific control of proteolysis especially in extracellular body fluids. In stark contrast unicellular organisms, both prokaryotic and eukaryotic consistently contain only few, if any, genes coding for putative peptidase inhibitors. This may seem perplexing in the light of the fact that these organisms produce large numbers of proteases of different catalytic classes with the genes constituting up to 6% of the total gene count with the average being about 3%. Apparently, however, a unicellular life-style is fully compatible with other mechanisms of regulation of proteolysis and does not require protein inhibitors to control their intracellular and extracellular proteolytic activity. So in prokaryotes occurrence of genes encoding different types of peptidase inhibitors is infrequent and often scattered among phylogenetically distinct orders or even phyla of microbiota. Genes encoding proteins homologous to alpha-2-macroglobulin (family I39), serine carboxypeptidase Y inhibitor (family I51), alpha-1-peptidase inhibitor (family I4) and ecotin (family I11) are the most frequently represented in Bacteria. Although several of these gene products were shown to possess inhibitory activity, with an exception of ecotin and staphostatins, the biological function of microbial inhibitors is unclear. In this review we present distribution of protein inhibitors from different families among prokaryotes, describe their mode of action and hypothesize on their role in microbial physiology and interactions with hosts and environment. KeywordsBacteria; Archaea; proteolytic enzymes; proteolysis; regulation I -Overview of mechanisms regulating proteolysisRegardless of the complexity of the organism, peptidases in general are essential at every stage in the life of every individual cell. Apart from non-specific protein degradation, peptidases are involved in highly sophisticated essential biological processes, both in prokaryotic andCorresponding author: Jan Potempa, PhD, DSc, University of Louisville School of Dentistry\, Oral Health and Systemic Disease, Louisville, KY, USA, Fax: (+1) 502-852-5572, jspote01@louisville.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBiochimie. Author manuscript; available in PMC 2011 November 1. Published in final edited form as:Biochimie. 2010 November ; 92(11): 1644-1656. doi:...

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“…(13) shows that the average squared fluctuations (amplitudes of motion) are inversely proportional to their associated frequencies of oscillation v k . This implies that the largest contribution to the atomic displacement comes from the lowest frequency normal modes [37].…”

Section: Normal Mode Analysismentioning

confidence: 99%

“…Avoiding entropy calculations has been a major trend in many computational biology studies due to the impractical computational demand associated with these calculations [11][12][13][14][15][16], particularly, for large biological systems and processes. These computational studies relied mainly on the concept of relative, rather than absolute binding energies.…”

Section: Introductionmentioning

confidence: 99%

Entropy in bimolecular simulations: A comprehensive review of atomic fluctuations-based methods

Kassem

Ahmed

El‐Sheikh

et al. 2015

Journal of Molecular Graphics and Modelling

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Molecular insight into pseudolysin inhibition using the MM-PBSA and LIE methods

Cited by 22 publications

References 66 publications

Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

Prokaryote-derived protein inhibitors of peptidases: A sketchy occurrence and mostly unknown function

Entropy in bimolecular simulations: A comprehensive review of atomic fluctuations-based methods

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