Multi-targeted therapy for leprosy: Insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy

Shanmugam, Anusuya; Natarajan, Jeyakumar

doi:10.1016/j.meegid.2012.08.013

Cited by 8 publications

(6 citation statements)

References 61 publications

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“…In recent years, Mur enzymes in Mtb have received attention as promising drug targets due to their essential requirement in the survival of the pathogen. 9,10,28,45,46 To identify Mur enzyme-specific inhibitors, an attempt was made in this study to screen compounds with previously demonstrated anti-Mtb activity. 45,47 MurB and MurE enzymes were selected because in Mtb , crystal structures of only these two Mur enzymes have been solved.…”

Section: Discussionmentioning

confidence: 99%

“…With this approach, the odds of gain of resistance to such drugs by the bacterium are very high. 9,10 In contrast, a microorganism would take longer to develop resistance against a molecule that can inhibit more than one of its essential proteins. Hence, finding a drug molecule that has multiple targets within the pathogen would not only require robust computational screening but also mandate the development of an assay method, where multiple enzymes (potential targets) can function optimally in a single reaction.…”

Section: Introductionmentioning

confidence: 99%

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Screening of Antitubercular Compound Library Identifies Inhibitors of Mur Enzymes in Mycobacterium tuberculosis

et al. 2020

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The rapid rise in the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) mandates the discovery of novel tuberculosis (TB) drugs. Mur enzymes, which are identified as essential proteins in Mtb and catalyze the cytoplasmic steps in the peptidoglycan biosynthetic pathway, are considered potential drug targets. However, none of the clinical drugs have yet been developed against these enzymes. Hence, the aim of this study was to identify novel inhibitors of Mur enzymes in Mycobacterium tuberculosis. We screened an antitubercular compound library of 684 compounds, using MurB and MurE enzymes of the Mtb Mur pathway as drug targets. For experimental validation, the top hits obtained on in silico screening were screened in vitro, using Mtb Mur enzyme-specific assays. In all, seven compounds were found to show greater than 50% inhibition, with the highest inhibition observed at 77%, and the IC50 for these compounds was found to be in the range of 28–50 μM. Compound 5175112 showed the lowest IC50 (28.69 ± 1.17 μM), and on the basis of (1) the binding affinity, (2) the stability of interaction noted on molecular dynamics simulation, and (3) an in vitro assay, MurE appeared to be its target enzyme. We believe that the overall strategy followed in this study and the results obtained are a good starting point for developing Mur enzyme-specific Mtb inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Screening of Antitubercular Compound Library Identifies Inhibitors of Mur Enzymes in Mycobacterium tuberculosis

et al. 2020

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“…In molecular modeling, the crystal structure, conformation and the orientation of lead molecule provides the binding energy of the target receptor and finally results in docking scores which aids in arriving at the best docked ligand structure. Thus docking studies play a significant role in rational designing of drugs and aids drug discovery process (Rother et al, 2006;Anusuya and Natarajan, 2012;Rask-Andersen et al, 2011;Akhila et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Maestro 9.4 as a Tool in the Structure Based Screening of Glycoalkaloids and Related Compounds, Targeting Aldose Reductase

Firdhouse¹,

Lalitha²

2015

Trends in Bioinformatics

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Diabetes mellitus is one of the alarming common diseases of this century. In India, according to the statistics of the International Diabetes Federation, 87 million of people are affected by Diabetes mellitus and this number is expected to cross 100 million by 2030. This has created a thrust for the development of new medicines. Recently, ban of pioglitazone, an oral anti-diabetic drug by Drugs Technical Advisory Board (DTAB) on account of its side effects, portrays the need for developing new drugs with less or no side effects. Cheminformatics tools assist in screening several millions of compounds and providing lead compounds in drug designing. This paper focuses on screening of lead compounds in arriving at newer drugs for Diabetes mellitus. Aldose reductase a cytosolic enzyme is the receptor to which selected lead compounds are docked. Glycoalkaloids (present in bitter melon) and related compounds were docked onto aldose reductase and based on the GLIDE score, structural modifications were carried out to arrive at the highest GLIDE score. A commercially available molecule recommended for Type 2 Diabetes mellitus was also taken for reference. Glycoalkaloids were found to possess high GLIDE score compared to standard. In order to analyze the competence of the Schrodinger software a comparison was made with an internet freeware Hex 6.3 version. The flexible receptor docking of Schrodinger was found to be more advantageous than the Hex 6.3. Key words: Diabetes mellitus, aldose reductase, glycoalkaloids, GLIDE score INTRODUCTIONHuman life span is on an increase and aging is also postponed in recent days. Innovative medicines play a profound role along with nutrition, sanitation and other public health measures in increasing the average life span of man. Still there are many of the most common human diseases that are not effectively treated by existing therapies. With the improved technologies, researchers are focusing on genes and proteins responsible for genetic disorders and common polygenic diseases such as diabetes, heart disease etc. The increased pressure from the cost of clinical investigations and insufficient sources of financial support in research promotes cheminformatics (Hughes et al., 2011;Van de Waterbeemd and Gifford, 2003;Guttula et al., 2011;Umamaheswari et al., 2012).In order to facilitate the speed and cost involved in the drug discovery, a number of computational methods are used. The successfulness of the methods depend on number of factors like ligand structure, target receptor structure etc. In molecular modeling, the crystal structure,

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“…Therefore, not only are new TB drugs required to combat the menace of antibiotic resistance, alternative approaches for finding new drugs are also important. One such approach that will have obvious advantages in clinical use is a multi-targeted therapy, where a single drug targets multiple enzymes in key metabolic pathways of the pathogen and hence reduces the probability of occurrence of drug-resistance 6 7 8 .…”

mentioning

confidence: 99%

“…Mtb encodes a series of pathways that are (i) unique to the bacterium, (ii) essential for its growth, (iii) absent in mammalian cells and hence are promising targets for the selective inhibition of pathogen growth while sparing the host with potentially reduced side effects 8 9 10 . The cell wall of Mtb is one such target, which is composed of three covalently linked macromolecules: peptidoglycan, arabinogalactan and mycolic acids 11 12 13 .…”

mentioning

confidence: 99%

Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis

Eniyan

Kumar

Rayasam

et al. 2016

Sci Rep

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The cell wall of Mycobacterium tuberculosis (Mtb) consists of peptidoglycan, arabinogalactan and mycolic acids. The cytoplasmic steps in the peptidoglycan biosynthetic pathway, catalyzed by the Mur (A-F) enzymes, involve the synthesis of UDP-n-acetylmuramyl pentapeptide, a key precursor molecule required for the formation of the peptidoglycan monomeric building blocks. Mur enzymes are indispensable for cell integrity and their lack of counterparts in eukaryotes suggests them to be promising Mtb drug targets. However, the caveat is that most of the current assays utilize a single Mur enzyme, thereby identifying inhibitors against only one of the enzymes. Here, we report development of a one-pot assay that reconstructs the entire Mtb Mur pathway in vitro and has the advantage of eliminating the requirement for nucleotide intermediates in the pathway as substrates. The MurA-MurF enzymes were purified and a one-pot assay was developed through optimization of successive coupled enzyme assays using UDP-n-acetylglucosamine as the initial sugar substrate. The assay is biochemically characterized and optimized for high-throughput screening of molecules that could disrupt multiple targets within the pathway. Furthermore, we have validated the assay by performing it to identify D-Cycloserine and furan-based benzene-derived compounds with known Mur ligase inhibition as inhibitors of Mtb MurE and MurF.

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Multi-targeted therapy for leprosy: Insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy

Cited by 8 publications

References 61 publications

Screening of Antitubercular Compound Library Identifies Inhibitors of Mur Enzymes in Mycobacterium tuberculosis

Screening of Antitubercular Compound Library Identifies Inhibitors of Mur Enzymes in Mycobacterium tuberculosis

Maestro 9.4 as a Tool in the Structure Based Screening of Glycoalkaloids and Related Compounds, Targeting Aldose Reductase

Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis

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