Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies

Velázquez‐Libera, José Luis; Murillo-López, Juliana A.; Torre, Alexander F. de la; Caballero, Julio

doi:10.3390/ijms20246133

Cited by 13 publications

(10 citation statements)

References 42 publications

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“…However, despite a potentially similar binding as phosphoramidon ( 1 ), the phenol moiety of 8 seems to be too far from Glu111 to establish a hydrogen bond. Our simulations are similar to those previously published for these dipeptides [ 35 ].…”

Section: Lasb Inhibitorssupporting

confidence: 88%

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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 Inhibitorssupporting

confidence: 88%

“…The binding site of LasB thus presents various features, which have been extensively described in the literature [ 35 ], and can help rationalize the activity and inspire the design of LasB inhibitors.…”

Section: Description Of the Active Site Of Lasbmentioning

confidence: 99%

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

et al. 2022

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“…In this section I am focused on identifying the recurrent interactions between ACE domain binding sites and their ligands, and the residues involved in these interactions. Interaction fingerprints (IFPs) is a very effective method for such analysis, with recent successful applications in diverse protein-ligand systems [84][85][86][87]. "Interaction Fingerprints Panel" of Maestro (Maestro 10.2.011, Schrödinger LLC) was used for constructing the IFPs as described in Singh et al [88,89].…”

Section: Interaction Fingerprints (Ifps) For Ace Inhibitors Derived Fmentioning

confidence: 99%

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Caballero

2020

Molecules

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The angiotensin-converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase, which has a direct involvement in the control of blood pressure by performing the hydrolysis of angiotensin I to produce angiotensin II. At the same time, ACE hydrolyzes other substrates such as the vasodilator peptide bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. In this sense, ACE inhibitors are bioactive substances with potential use as medicinal products for treatment or prevention of hypertension, heart failures, myocardial infarction, and other important diseases. This review examined the most recent literature reporting ACE inhibitors with the help of molecular modeling. The examples exposed here demonstrate that molecular modeling methods, including docking, molecular dynamics (MD) simulations, quantitative structure-activity relationship (QSAR), etc, are essential for a complete structural picture of the mode of action of ACE inhibitors, where molecular docking has a key role. Examples show that too many works identified ACE inhibitory activities of natural peptides and peptides obtained from hydrolysates. In addition, other works report non-peptide compounds extracted from natural sources and synthetic compounds. In all these cases, molecular docking was used to provide explanation of the chemical interactions between inhibitors and the ACE binding sites. For docking applications, most of the examples exposed here do not consider that: (i) ACE has two domains (nACE and cACE) with available X-ray structures, which are relevant for the design of selective inhibitors, and (ii) nACE and cACE binding sites have large dimensions, which leads to non-reliable solutions during docking calculations. In support of the solution of these problems, the structural information found in Protein Data Bank (PDB) was used to perform an interaction fingerprints (IFPs) analysis applied on both nACE and cACE domains. This analysis provides plots that identify the chemical interactions between ligands and both ACE binding sites, which can be used to guide docking experiments in the search of selective natural components or novel drugs. In addition, the use of hydrogen bond constraints in the S2 and S2′ subsites of nACE and cACE are suggested to guarantee that docking solutions are reliable.

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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: Methodsmentioning

confidence: 99%

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

Magpantay

Malaluan

Manzano

et al. 2021

Plants

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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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Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies

Cited by 13 publications

References 42 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

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

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

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