A structural comparative approach to identifying novel antimalarial inhibitors

Franco, Jimmy; Blackie, Margaret A.L.; Tóth, Dávid; Smith, Peter J.; Capuano, Joseph; Fastnacht, Kurt V.; Berkes, Charlotte A.

doi:10.1016/j.compbiolchem.2013.04.002

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…PfUCHL3 is one such promising member of Plasmodium deubiquitinase family, whose absence exhibits a lethal effect on parasite survival, thereby, validating its utmost importance as a therapeutic target 46 . A report by Franco et al, identified inhibitors against PfUCHL3 from the ZINC database by virtual screening 73 . Unfortunately, the study lacked enzymatic validation and biological assay of the identified hits.…”

Section: Discussionmentioning

confidence: 99%

Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity

Bharti

Singal

Saini

et al. 2022

Sci Rep

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Malaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.

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Section: Discussionmentioning

confidence: 99%

Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity

Bharti

Singal

Saini

et al. 2022

Sci Rep

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“…Additionally, structural information allows more rapid rational design approaches to be utilized. Thus reducing computational requirements by providing focused targeted areas on proteins to combat food and crop losses [69,70]. These single studies can be expanded to similar molecular sets within the pathogen, when key structural and functional comparisons are utilized from the wealth of already available genomic data.…”

Section: Discussionmentioning

confidence: 99%

Molecular Dynamics Simulations of Phytopthora sojae Avirulence Factor 5, PsAvh5, Define Membrane Binding, Inositolphosphate-3’-phosphate Interactions and Protein Mechanics

2021

Preprint

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Phytopthora Avirulence proteins are a primary target for development of rational chemical and biological control of some of the most devastating plant pathogens. Despite the sequencing of entire genomes, and characterization of many of these proteins at the chemical level, many questions remain regarding actual chemical and biological interactions involved. In addition, disputed roles of ligands, such as Inositolphosphate-3’-phosphate and amino acids of important function remain unclear. To address some of these issues, we developed molecular models from structural elements and published data for Phytopthora sojae avirulence protein 5. Molecular dynamics simulations are used to study protein function, interactions involved primarily with lipids and membranes, and inositol derivatives. Our findings indicate that the protein is stable as a monomer, and in a dimeric form. Also, that these proteins interact with Inositolphosphate-3’phosphate as a necessary membrane element, in binding. We identified several amino acids of importance, additional to defining the mechanical features of the protein within the binding process to different membranes. A high affinity, comparable to other membrane surface binding molecules of −219.54 Kcal for the dimer, and −176.61 for the monomer were determined. With either form, we found the inositolphosphate-3’-phosphate to be essential in the membrane binding process. Our findings answer some of the debated questions while creating a point to further test avirulence proteins in general for functional aspects. Additionally, the structures and data can be utilized to provide a better starting point for rational design approaches to control this pathogen.

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“…The corresponding author has worked with teams using virtual screening on several projects [13]. In one such study, the target was an essential enzyme found in Plasmodium sp., the causative agent of malaria [14]. The opensource docking simulation program AutoDock Vina, designed at the Scripps Research Institute, was used to screen the full_nci_ALL_TAUTOMERS_2011 library of about 320,000 chemical compounds from the ZINC database against the enzyme PfUCHL3 [6,15].…”

Section: Related Workmentioning

confidence: 99%

Identification of Inhibitors of Fatty Acid Synthesis Enzymes in Mycobacterium Smegmatis

Priest

Oldham

Lewis

et al. 2015

JOCSE

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Antibiotic-resistant strains of Mycobacterium tuberculosis have rendered some of the current treatments for tuberculosis ineffective, creating a need for new treatments. Today, the most efficient way to find new drugs to treat tuberculosis and other diseases is to use virtual screening to quickly consider millions of potential drug candidates and filter out all but the ones most likely to inhibit the disease. These top hits can then be tested in a traditional wet lab to determine their potential effectiveness. Using supercomputers, we screened over 4 million potential drug molecules against each of two enzymes that are critical to the survival of Mycobacterium tuberculosis. During this process, we determined the top candidate molecules to test in the wet lab.

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A structural comparative approach to identifying novel antimalarial inhibitors

Cited by 6 publications

References 30 publications

Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity

Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity

Molecular Dynamics Simulations of Phytopthora sojae Avirulence Factor 5, PsAvh5, Define Membrane Binding, Inositolphosphate-3’-phosphate Interactions and Protein Mechanics

Identification of Inhibitors of Fatty Acid Synthesis Enzymes in Mycobacterium Smegmatis

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