Identification of Novel Inhibitors of UDP‐Galactopyranose Mutase by Structure‐Based Virtual Screening

Partha, Sarathy Karunan; Sadeghi-Khomami, Ali; Cren, Sylvaine; Robinson, Richard I.; Woodward, Simon; Slowski, Kate; Berast, Lindsey; Zheng, Blake; Thomas, Neil R.; Sanders, D.A.R.

doi:10.1002/minf.201100085

Cited by 9 publications

(7 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a virtual screening using various computational tools toward the identification of inhibitors against Ec UGM (also Kp UGM and Mt UGM) was applied to a small-molecule library comprised of 84,000 compounds (LeadQuest,Tripos, Inc.) [57]. A total of 13 compounds (0.015% of the library) were identified as positive hits and tested for inhibitory activity toward Kp UGM and Mt UGM.…”

Section: In Silico Drug Design and Its Applications To Ugmmentioning

confidence: 99%

Targeting UDP-Galactopyranose Mutases from Eukaryotic Human Pathogens

Kizjakina¹,

Tanner²,

Sobrado³

2013

CPD

View full text Add to dashboard Cite

UDP-Galactopyranose mutase (UGM) is a unique flavin-dependent enzyme that catalyzes the conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). The product of this reaction is the precursor to Galf, a major component of the cell wall and of cell surface glycoproteins and glycolipids in many eukaryotic and prokaryotic human pathogens. The function of UGM is important in the virulence of fungi, parasites, and bacteria. Its role in virulence and its absence in humans suggest that UGM is an ideal drug target. Significant structural and mechanistic information has been accumulated on the prokaryotic UGMs; however, in the past few years the research interest has shifted to UGMs from eukaryotic human pathogens such as fungi and protozoan parasites. It has become clear that UGMs from prokaryotic and eukaryotic organisms have different structural and mechanistic features. The amino acid sequence identity between these two classes of enzymes is low, resulting in differences in oligomeric states, substrate binding, active site flexibility, and interaction with redox partners. However, the unique role of the flavin cofactor in catalysis is conserved among this enzyme family. In this review, recent findings on eukaryotic UGMs are discussed and presented in comparison with prokaryotic UGMs.

show abstract

Section: In Silico Drug Design and Its Applications To Ugmmentioning

confidence: 99%

Targeting UDP-Galactopyranose Mutases from Eukaryotic Human Pathogens

Kizjakina¹,

Tanner²,

Sobrado³

2013

CPD

View full text Add to dashboard Cite

show abstract

“…Several approaches have been adopted to design UGM inhibitors ,. Among them, mechanism‐based inhibitors,,,, substrate analogues inhibitors,, and heterocyclic molecules obtained from screening of chemical libraries or virtual screening have also emerged.…”

Section: Introductionmentioning

confidence: 99%

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Villaume

N’Go

et al. 2017

Chemistry A European J

View full text Add to dashboard Cite

This study reports a novel class of inhibitors of uridine 5'-diphosphate (UDP) galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids are potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed a structure-activity relationship analysis to be performed and which functional groups and structural elements were required for UGM inhibition could be determined. The binding mode of one of the best inhibitors was found to be noncompetitive. Docking simulations indicated that this molecule was likely to bind UGM in its open conformation, in a cavity recently identified as a "druggable" pocket. Importantly, two of the best inhibitors of the M. tuberculosis UGM displayed moderate activity against whole M. tuberculosis cells. This study reports the first natural products that act as inhibitor of UGM. Given the importance of natural products in medicinal chemistry, these results create new opportunities for the discovery of new antitubercular agents.

show abstract

“…Several studies have been performed in recent years to identify UGM inhibitors . These studies were performed with prokaryotic UGMs, mainly in P. pneumoniae and M. tuberculosis UGM, and no information about eukaryotic UGM inhibitors can be found in the literature.…”

Section: Introductionmentioning

confidence: 99%

Substrate‐dependent dynamics of UDP‐galactopyranose mutase: Implications for drug design

et al. 2013

View full text Add to dashboard Cite

Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that represents one of the major health challenges of the Latin American countries. Successful efforts were made during the last few decades to control the transmission of this disease, but there is still no treatment for the 10 million adults in the chronic phase of the disease. In T. cruzi, as well as in other pathogens, the flavoenzyme UDP-galactopyranose mutase (UGM) catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, a precursor of the cell surface b-galactofuranose that is involved in the virulence of the pathogen. The fact that UGM is not present in humans makes inhibition of this enzyme a good approach in the design of new Chagas therapeutics. By performing a series of computer simulations of T. cruzi UGM in the presence or absence of an active site ligand, we address the molecular details of the mechanism that controls the uptake and retention of the substrate. The simulations suggest a modular mechanism in which each moiety of the substrate controls the flexibility of a different protein loop. Furthermore, the calculations indicate that interactions with the substrate diphosphate moiety are especially important for stabilizing the closed active site. This hypothesis is supported with kinetics measurements of site-directed mutants of T. cruzi UGM. Our results extend our knowledge of UGM dynamics and offer new alternatives for the prospective design of drugs.

show abstract

Identification of Novel Inhibitors of UDP‐Galactopyranose Mutase by Structure‐Based Virtual Screening

Cited by 9 publications

References 51 publications

Targeting UDP-Galactopyranose Mutases from Eukaryotic Human Pathogens

Targeting UDP-Galactopyranose Mutases from Eukaryotic Human Pathogens

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Substrate‐dependent dynamics of UDP‐galactopyranose mutase: Implications for drug design

Contact Info

Product

Resources

About