Molecular modeling of a series of dehydroquinate dehydratase type II inhibitors of Mycobacterium tuberculosis and design of new binders

Miranda, Paulo Henrique de Santana; Lourenço, Estela Mariana Guimarães; Morais, Alexander M. S.; Oliveira, Pedro Igor Câmara de; Silverio, Priscilla S. de S. N.; Jordão, Alessandro K.; Barbosa, Euzébio Guimarães

doi:10.1007/s11030-019-10020-1

Cited by 4 publications

(5 citation statements)

References 65 publications

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“…In recent years, one of the most important advances in the development of medicines has been the implementation of in silico methodologies [ 29 ]. The Molecular Docking methodology explores the behavior of small molecules at the binding site of a target protein.…”

Section: Discussionmentioning

confidence: 99%

In Silico Study, Physicochemical, and In Vitro Lipase Inhibitory Activity of α,β-Amyrenone Inclusion Complexes with Cyclodextrins

Oliveira

Menezes

Silva

et al. 2021

IJMS

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α,β-amyrenone (ABAME) is a triterpene derivative with many biological activities; however, its potential pharmacological use is hindered by its low solubility in water. In this context, the present work aimed to develop inclusion complexes (ICs) of ABAME with γ- and β-cyclodextrins (CD), which were systematically characterized through molecular modeling studies as well as FTIR, XRD, DSC, TGA, and SEM analyses. In vitro analyses of lipase activity were performed to evaluate possible anti-obesity properties. Molecular modeling studies indicated that the CD:ABAME ICs prepared at a 2:1 molar ratio would be more stable to the complexation process than those prepared at a 1:1 molar ratio. The physicochemical characterization showed strong evidence that corroborates with the in silico results, and the formation of ICs with CD was capable of inducing changes in ABAME physicochemical properties. ICs was shown to be a stronger inhibitor of lipase activity than Orlistat and to potentiate the inhibitory effects of ABAME on porcine pancreatic enzymes. In conclusion, a new pharmaceutical preparation with potentially improved physicochemical characteristics and inhibitory activity toward lipases was developed in this study, which could prove to be a promising ingredient for future formulations.

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Section: Discussionmentioning

confidence: 99%

In Silico Study, Physicochemical, and In Vitro Lipase Inhibitory Activity of α,β-Amyrenone Inclusion Complexes with Cyclodextrins

Oliveira

Menezes

Silva

et al. 2021

IJMS

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“…Inspired by these findings, our research group developed a class of anthranilate-like compounds (Figure 5) to improve the activity and reduce the cytotoxicity of 6-FABA [38]. Our strategy was to replace the carboxylic moiety of 6-FABA with different bioisosters, including hydroxamates (3-4), oxadiazoles and tetrazoles (5)(6), amides (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), hydrazides , aryl hydrazide hydrochlorides (40)(41), and trifluoromethyl amines (42-44) (Figure 5). When tested in vivo on a murine model of TB infection, the admin and its ethyl ester resulted in a significant reduction in the bacterial lo spleens (10-fold reduction relative to the control) [6], suggesting that t biosynthesis by an anthranilate-like compound synergizes with response to Mtb infection in vivo.…”

Section: Inhibitors Of Trp Biosynthesismentioning

confidence: 99%

“…Inspired by research group developed a class of anthranilate-like compounds (F the activity and reduce the cytotoxicity of 6-FABA [38]. Our strategy carboxylic moiety of 6-FABA with different bioisosters, including h oxadiazoles and tetrazoles (5)(6), amides (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), hydrazides (19-3 hydrochlorides (40-41), and trifluoromethyl amines (42-44) (Figure 5) When tested in vivo on a murine model of TB infection, the administration of 6-FAB and its ethyl ester resulted in a significant reduction in the bacterial load in infected m spleens (10-fold reduction relative to the control) [6], suggesting that the alteration of T biosynthesis by an anthranilate-like compound synergizes with the host immu response to Mtb infection in vivo. 6-FABA, the only well-characterized compound, w thought to inhibit either the formation of anthranilate by TrpE or its modification by Trp Subsequent work suggested that the toxic mechanism of 6-FABA occurs downstrea potentially inhibiting a subsequent step or forming fluoro-Trp that is then incorpora into polypeptides, causing global protein stress [37].…”

Section: Inhibitors Of Trp Biosynthesismentioning

confidence: 99%

“…Inspired by these findings, o research group developed a class of anthranilate-like compounds (Figure 5) to impro the activity and reduce the cytotoxicity of 6-FABA [38]. Our strategy was to replace carboxylic moiety of 6-FABA with different bioisosters, including hydroxamates (3oxadiazoles and tetrazoles (5)(6), amides (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), hydrazides , aryl hydraz hydrochlorides (40)(41), and trifluoromethyl amines (42-44) (Figure 5). The MICs against Mtb H37Rv ranged from 0.625 to >50 µM, with some analogu showing sub-micromolar activities and low cytotoxicities in Vero cells.…”

Section: Inhibitors Of Trp Biosynthesismentioning

confidence: 99%

“…The availability of structural information about the first five enzymes of this pathway has raised the possibility of rational structure-based drug design targeting these enzymes. Even though virtual screenings have generated a growing number of potential inhibitors [ 17 , 18 , 19 ], there are only a few recent reports about their effective inhibition against Mtb [ 20 ]. The only two compounds with confirmed activity against Mtb are IMB-T130 and IMB-SD62 [ 21 ] ( Figure 2 ), inhibiting DHQS and SD, respectively.…”

Section: Inhibitors Of Amino Acid Biosynthesismentioning

confidence: 99%

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Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

Guida,

Tammaro,

Quaranta

et al. 2024

Pharmaceutics

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According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A major concern is the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains, fueled by the length of anti-TB treatment and HIV comorbidity. Innovative anti-TB agents acting with new modes of action are the only solution to counteract the spread of resistant infections. To escape starvation and survive inside macrophages, Mtb has evolved to become independent of the host by synthesizing its own amino acids. Therefore, targeting amino acid biosynthesis could subvert the ability of the mycobacterium to evade the host immune system, providing innovative avenues for drug discovery. The aim of this review is to give an overview of the most recent progress in the discovery of amino acid biosynthesis inhibitors. Among the hits discovered over the past five years, tryptophan (Trp) inhibitors stand out as the most advanced and have significantly contributed to demonstrating the feasibility of this approach for future TB drug discovery. Future efforts should be directed at prioritizing the chemical optimization of these hits to enrich the TB drug pipeline with high-quality leads.

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Multitargeting: An Alternative Approach to Tackle Multidrug Resistance in Tuberculosis

Patra

Hazra

Hazarika

2023

CDT

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Background: The prevalence of drug-resistant organisms has steadily increased over the past few decades worldwide. Especially in tuberculosis (TB) disease, the problems of co-morbidity and the rapid emergence of multidrug resistance have necessitated the development of multitarget-based therapeutic regimens. Several multitargeting compounds against Mycobacterium tuberculosis (Mtb) have been studied through novel in silico tools but these have rendered reduced efficacy in clinical trials. The authors have focussed on many exotic targets belonging to crucial Mtb survival pathways whose molecular structures and functions are underexplored. Likewise, insights into the hidden possibilities of promiscuous compounds from natural products or repurposed drugs to inhibit other cellular proteins apart from their validated targets are also depicted in this review. In addition to the existing line of drugs currently recommended for multidrug-resistant TB, newer host-directed therapies could also be fruitful. Furthermore, several challenges, including safety/efficacy ratios of multitarget compounds highlighted here, can also be circumnavigated by researchers to design “smart drugs” for improved tuberculosis therapeutics. Conclusion: A holistic approach towards alleviating the existing drawbacks of drug discovery in drug-resistant TB has been outlined. Finally, considering the current needs, the authors have put forward an overall summary of possible trends in multitargeting that are significant for futuristic therapeutic solutions.

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Molecular modeling of a series of dehydroquinate dehydratase type II inhibitors of Mycobacterium tuberculosis and design of new binders

Cited by 4 publications

References 65 publications

In Silico Study, Physicochemical, and In Vitro Lipase Inhibitory Activity of α,β-Amyrenone Inclusion Complexes with Cyclodextrins

In Silico Study, Physicochemical, and In Vitro Lipase Inhibitory Activity of α,β-Amyrenone Inclusion Complexes with Cyclodextrins

Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

Multitargeting: An Alternative Approach to Tackle Multidrug Resistance in Tuberculosis

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