Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain (original) (raw)
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Tuberculosis (Edinburgh, Scotland), 2018
One of the major mechanisms followed by the therapeutic agents to target the causative organism of TB, Mycobacterium tuberculosis, involves disruption of its DNA replication cycle. The process of replication involves two steps, i.e., breakage and reunion of DNA at gyrase A (GyrA) domain and ATP hydrolysis at gyrase B (GyrB) domain, both occur simultaneously. Current therapy for multi-drug resistant TB (MDR-TB) involves FDA approved, fluoroquinolone-based antibiotics, which act by targeting replication process at GyrA domain. However, resistance against fluoroquinolones due to mutations in the GyrA domain has limited the use of this therapy and shifted the focus of research community on GyrB domain. Thus, in the present study novel chemotherapeutic agents for resistant TB were designed by exploring GyrB domain using in silico techniques. Pharmacophore model of GyrB domain was employed for screening an In-house database. Followed by cross-screening via a qualitative Hip-Hop pharmacoph...
Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis
Biochemical Journal, 2020
Drug repurposing is an alternative avenue for identifying new drugs to treat tuberculosis (TB). Despite the broad-range of anti-tubercular drugs, the emergence of multi-drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) H37Rv, as well as the significant death toll globally, necessitates the development of new and effective drugs to treat TB. In this study, we have employed a drug repurposing approach to address this drug resistance problem by screening the drugbank database to identify novel inhibitors of the Mtb target enzyme, DNA gyrase. The compounds were screened against the ATPase domain of the gyrase B subunit (MtbGyrB47), and the docking results showed that echinacoside, doxorubicin, epirubicin, and idarubicin possess high binding affinities against MtbGyrB47. Comprehensive assessment using fluorescence spectroscopy, surface plasmon resonance spectroscopy (SPR), and circular dichroism (CD) titration studies revealed echinacoside as a pot...
Chemical classes targeting energy supplying GyrB domain of Mycobacterium tuberculosis
Tuberculosis, 2018
Tuberculosis (TB) is contagious in nature and immunocompromised patients have a higher probability of developing TB. The occurrence of drug resistance, has led to serious health concerns in the management of TB. In order to combat resistant tuberculosis there is an urgent need of identifying new drug targets and new drug combinations for the effective management and reduction in the duration of TB treatment. Targeting DNA gyrase that is involved in bacterial replication cycle, provides one rationale approach. Various fluoroquinolone based drugs have shown promising effect against DNA gyrase enzyme and in turn were successful in combat against MDR TB. However, GyrA domain mutations based resistance towards fluoroquinolones has put a question mark over current therapies for tuberculosis. Fluoroquinolones target GyrA domain of bacterial DNA gyrase therefore targeting DNA GyrB domain may overcome this resistance issue, establishing it as an attractive target. This review is a compilation of current research efforts on energy supplying domain of Mycobacterium tuberculosis that could provide breakthrough in development of more potent Mtb DNA GyrB inhibitors.
Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis
Journal of Antimicrobial Chemotherapy, 2012
Objectives: New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance to existing agents and shorten the duration of therapy. Targeting DNA gyrase is a clinically validated therapeutic approach using fluoroquinolone antibiotics to target the gyrase subunit A (GyrA) of the heterotetramer. Increasing resistance to fluoroquinolones has driven interest in targeting the gyrase subunit B (GyrB), which has not been targeted for TB. The biological activities of two potent small-molecule inhibitors of GyrB have been characterized to validate its targeting as a therapeutic strategy for treating TB.
Bioorganic & medicinal chemistry letters, 2014
Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC 50 2 nM) along with potent cellular activity (MIC = 0.1 lM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.
In silico effective inhibition of galtifloxacin on built Mtb-DNA gyrase
Journal of Bioinformatics and Sequence Analysis, 2009
Tuberculosis (TB) resurged in the late 1980s and now kills approximately 3 million people a year. The reemergence of tuberculosis as a public health threat has created a need to develop new antimycobacterial agents. The Mtb-DNA Gyrase is an attractive target for development of new drugs due to its indispensable role in catalyzing the negative supercoiling of DNA and is essential for efficient DNA replication, transcription and recombination. Fluoroquinolone families of inhibitors are developed against the Mtb-DNA gyrase which show the best inhibition with DNA gyrase in the past. Due to the development of Multi-drug resistant Mycobacterium tuberculosis strains, the drugs showed less efficiency on the targets, recently, a new flouroquinolone inhibitor was identified (Galtifloxacin), which shown best inhibition. In this study we carried out Homology model of 0 Mtb-DNA gyrase, secondary structure analysis and active site analysis. Docking studies were also carried out with the Galtifloxacin and Amifloxacin and are helpful for further studies on the development of novel drugs against Mtb-DNA gyrase.
Antimicrobial Agents and Chemotherapy, 2014
ABSTRACTMoxifloxacin has shown excellent activity against drug-sensitive as well as drug-resistant tuberculosis (TB), thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which killMycobacterium tuberculosisthrough inhibition of ATPase activity catalyzed by the GyrB domain of DNA gyrase. A homology model of theM. tuberculosisH37Rv GyrB domain was used for deciphering the structure-activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through cocrystal structure studies with theMycobacterium smegmatisGyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC50) of <5 nM, an MIC of 0.03 μg/ml againstM. tuberculosisH37Rv, and an MIC90of <0.25 μg/ml against 99 drug-resistant clinical isolates ofM. tuber...
Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs
Antimicrobial Agents and Chemotherapy, 2015
One way to speed up the TB drug discovery process is to search for antitubercular 23 activity amongst compound series that already possess some of the key properties 24 needed in anti-infective drug discovery such as whole cell activity and oral absorption. 25 Herein we present MGI's, a new series of Mycobacterium tuberculosis Gyrase 26 (TDR), is defined by resistance to all second-line drug classes. TDR cases have been 48 increasingly reported in the clinic (6,7).
Journal of Biomolecular Structure & Dynamics, 2010
Mycobacterium tuberculosis is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of M. tuberculosis infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-TB agents are necessary. Therefore, dUTpase was selected as a target enzyme to combat M. tuberculosis. In this work, molecular modeling methods involving docking and QM/MM calculations were carried out to investigate the binding orientation and predict binding affinities of some potential dUTpase inhibitors. Our results suggest that the best potential inhibitor investigated, among the compounds studied in this work, is the compound dUPNPP. Regarding the reaction mechanism, we concluded that the decisive stage for the reaction is the stage 1. Furthermore, it was also observed that the compounds with a -1 electrostatic charge presented lower activation energy in relation to the compounds with a -2 charge.