Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Benítez, Diego; Franco, J.; Sardi, Florencia; Leyva, Alejandro; Durán, Rosario; Choi, Gahee; Yang, Gyongseon; Kim, Tae-Hee; Kim, Namyoul; Heo, Jinyeong; Kim, Kideok; Lee, Honggun; Choi, Inhee; Radu, Constantin; Shum, David; No, Joo Hwan; Comini, Marcelo A.

doi:10.1080/14756366.2022.2045590

Cited by 15 publications

(16 citation statements)

References 69 publications

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“…Notably, the strictly conserved residues important for the catalysis of ATP at S1 and orientation of ligands at S3 comprising Arg313, Ser336, and Cys341 (nonconserved) are affected due to the dynamics of Arg569 upon ligand binding Figure . Findings from MD simulations not just highlight the critical role of Arg569 but also indicate the presence of a possible allosteric site S4 near the catalytic site S3 of TSA that has been reported in multiple experimental studies. , In the same context, the study conducted by Koch et al reports the possibility of an allosteric site, concurrent with the current study that should undergo experimental and NMR crystallography in future studies, especially in connection to the orientation of Arg569 (horizontally aligned).…”

Section: Resp Chargessupporting

confidence: 69%

Quantum Dynamics and Bi Metal Force Field Parameterization Yielding Significant Antileishmanial Targets

Zaman

Azam

2023

J. Chem. Inf. Model.

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Amid emerging drug resistance to metal inhibitors, high toxicity, and onerous drug delivery procedures, the computational design of alternate formulations encompassing functional metal-containing compounds greatly relies on large-scale atomistic simulations. Simulations particularly with Au(I), Ag, Bi(V), and Sb(V) pose a major challenge to elucidate their molecular mechanism due to the absence of force field parameters. This study thus quantum mechanically derives force field parameters of Bi(V) as an extension of the previous experimental study conducted on heteroleptic triorganobismuth(V) biscarboxylates of type [BiR3(O2CR′)2]. We have modeled two organo-bismuth(V) carboxylates, which are optimized and parameterized along with the famous pentavalent antimonial drug: meglumine antimoniate using quantum mechanics original Seminarian methods with the SBKJC effective core potential (ECP) basis set. Furthermore, molecular dynamics (MD) simulations of bismuth- and antimony-containing compounds in complex with two enzymes, trypanothione synthetase-amidase (TSA) and trypanothione reductase, are performed to target the (T(SH)2) pathway at multiple points. MD simulations provide novel insights into the binding mechanism of TSA and highlight the role of a single residue Arg569 in modulating the ligand dynamics. Moreover, the presence of an ortho group in a ligand is emphasized to facilitate interactions between Arg569 and the active site residue Arg313 for higher inhibitory activity of TSA. This preliminary generation of parameters specific to bismuth validated by simulations in replica will become a preamble of future computational and experimental research work to open avenues for newer and suitable drug targets.

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Section: Resp Chargessupporting

confidence: 69%

Quantum Dynamics and Bi Metal Force Field Parameterization Yielding Significant Antileishmanial Targets

Zaman

Azam

2023

J. Chem. Inf. Model.

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“…Kinetic, thermodynamic and computational approaches suggested that paullones occupy the Spd/Gsp binding site of TryS [ 26 , 48 ]. Thus, the paullone derivatives were docked into the Spd/Gsp site to analyse an alternative plausible binding mode.…”

Section: Resultsmentioning

confidence: 99%

The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones

Ihnatenko,

Müller,

Orban

et al. 2023

PLoS ONE

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Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids’ unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class.

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“…The study was performed as per the modified method described by Benitez et al 2022 [25] . The inhibition studies were performed with the inhibitors (allopurinol, chrysophanol and OMC) at two different assay conditions.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Xanthine oxidase by 1-O-methyl chrysophanol, a hydroxyanthraquinone isolated fromAmycolatopsis thermoflavaICTA 103

Batchu¹,

Reddi

Surapaneni³

et al. 2023

Preprint

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Hyperuricemia caused by elevated levels of serum uric acid is responsible for implication of gout and other associated disorders that influence the human health. So far, Xanthine oxidase (XO) inhibitors are the choice of first line drugs for the treatment of hyperuricemia. The objective of the present study was to isolate a potent XO inhibitor from the actinobacteria and to evaluate its inhibitory mechanism. Initially, XO was isolated from bovine milk using standard protocol and enzyme kinetics were evaluated. Thereafter, culture filtrates of actinobacteria (Amycolatopsis thermoflavaICTA 103),Streptomyces luteireticuliICTA 16,Streptomyces kurssanoviiICTA165 andAmycolatopsis luridaICTA 194) were screened for XO inhibition usingin vitroqualitative NBT plate assay followed by extraction and purification of potent inhibitor 1-O-methyl chrysophanol (OMC), from the culture filtrate ofAmycolatopsis thermoflavaICTA 103, which belongs to hydroxy anthraquinones (HAQ) family. Further,in silicomolecular model building was performed to study the binding affinity of OMC towards XO followed by quantitativein vitrospectroscopic assays. The molecular building study explored the mechanistic view of binding interaction between inhibitor & enzyme and the results were corroborates with thein vitrokinetic study. Thein vitroresults revealed the significant enzyme inhibition potential of OMC with an IC50andKivalue of 24.8 ± 0.072 µM & 2.218 ± 0.3068 µM respectively. These results are comparable to standard allopurinol, however, more significant than its structural analog, chrysophanol. The kinetic analysis revealed that OMC is a reversible slow binding inhibitor and the Lineweaver - Burkplot analysis showed mixed type inhibition of OMC against XO. These results are in agreement with chrysophanol. Findings of this study proposed a new derivative of HAQ in the pipeline of hyperuricemia therapeutic drug candidates.

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Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

Cited by 15 publications

References 69 publications

Quantum Dynamics and Bi Metal Force Field Parameterization Yielding Significant Antileishmanial Targets

Quantum Dynamics and Bi Metal Force Field Parameterization Yielding Significant Antileishmanial Targets

The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones

Inhibition of Xanthine oxidase by 1-O-methyl chrysophanol, a hydroxyanthraquinone isolated fromAmycolatopsis thermoflavaICTA 103

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