共查询到20条相似文献,搜索用时 31 毫秒
1.
Teodorico C. Ramalho Melissa S. Caetano Daniela Josa Gustavo P. Luz Elisangela A. Freitas Elaine F. F. da Cunha 《Journal of biomolecular structure & dynamics》2013,31(6):907-917
Abstract 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. 相似文献
2.
Elaine F. F. da Cunha Edilaine F. Barbosa Aline A. Oliveira Teodorico C. Ramalho 《Journal of biomolecular structure & dynamics》2013,31(5):619-625
Abstract Mycobacterium tuberculosis (Mt) is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of Mt infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-tuberculosis agents are necessary. Therefore, DNA gyrase was selected as a target enzyme to combat Mt. In this work, the first three-dimensional molecular model of the hypothetical structures for the Mycobacterium tuberculosis DNA gyrase (mtDNAg) was elucidated by a homology modeling method. In addition, the orientations and binding affinities of some gatifloxacin analogs with those new structures were investigated. Our findings could be helpful for the design of new more potent gatifloxacin analogs. 相似文献
3.
Fatty acid synthesis is essential for cell growth and viability. The 3-oxoacyl-acyl carrier protein synthase II (KAS II) from
Mycobacterium tuberculosis catalyses initiation of the fatty acid synthesis pathway by condensation of acyl CoA and mycolic acid during the elongation
phase. KAS II is a key regulator of bacterial fatty acid synthesis, and a promising target in the search for potent antibacterial
drugs. Homology modelling was used to generate the 3-D protein structure using the known crystal structure, and the stereochemical
quality of KAS II was validated. Effective drugs were selected that target the active amino acid residues of KAS II. The drugs
thiolactomycin, thiophenone and the multidrug cerulenin isoniazed were found to be more potent for inhibition of M. tuberculosis due to the robust binding affinity of their protein–drug interactions. KAS II enzymes of M. tuberculosis and other species of Mycobacterium are conserved, as revealed by their close phylogenetic relationships. This study may provide new insights towards understanding
the 3-D structural conformation and active amino acids of KAS II, thus providing rationale for the design of novel antibacterial
drugs. 相似文献
4.
Zhenhai Pan Ying Wang Xi Gu Maosheng Cheng 《Journal of biomolecular structure & dynamics》2020,38(16):4733-4745
AbstractCytochrome bcc complex is important for ATP synthesis and cellular activity, as a crucial step in the terminal reduction of oxygen in aerobic electron transport chains. The b subunit of cytochrome bcc complex (QcrB) has been reported as a promising anti-tuberculosis target, with many novel anti-tuberculosis scaffolds reported. However, the 3D structure of mycobacterium tuberculosis (M. tuberculosis) QcrB has not been released, making it hard to understand the interactions between QcrB and its inhibitors as well as to develop novel anti-tuberculosis scaffolds. Herein we built the optimal homology model of M. tuberculosis QcrB using the M. smegmatis QcrB structure as template, which was refined through all-atom molecular dynamics simulation. Then, the binding modes of known inhibitors were predicted through molecular docking method, along with molecular dynamics simulation and binding free energy calculation to verify the accuracy of docking results and stability of the protein-inhibitor complexes. The informative key residues within QcrB site enabled us to perform structure-based virtual library screening to obtain potential M. tuberculosis QcrB inhibitors, which were validated through molecular dynamics simulation and MM-GBSA calculation and analyzed through pharmacokinetic properties prediction. Our research would provide a deeper insight into the interactions between M. tuberculosis QcrB and its inhibitors, which boosts to develop novel therapy against tuberculosis.Communicated by Ramaswamy H. Sarma 相似文献
5.
Background
Mycobacterium tuberculosis kills approximately 2 million people each year and presents an urgent need to identify new targets and new antitubercular drugs. Thymidylate synthase (TS) enzymes from other species offer good targets for drug development and the M. tuberculosis genome contains two putative TS enzymes, a conventional ThyA and a flavin-based ThyX. In M. tuberculosis, both TS enzymes have been implicated as essential for growth, either based on drug-resistance studies or genome-wide mutagenesis screens. To facilitate future small molecule inhibitors against these proteins, a detailed enzymatic characterization was necessary.Methodology/Principal Findings
After cloning, overexpression, and purification, the thymidylate-synthesizing ability of ThyA and ThyX gene products were directly confirmed by HPLC analysis of reaction products and substrate saturation kinetics were established. 5-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) was a potent inhibitor of both ThyA and ThyX, offering important clues to double-targeting strategies. In contrast, the folate-based 1843U89 was a potent inhibitor of ThyA but not ThyX suggesting that it should be possible to find ThyX-specific antifolates. A turnover-dependent kinetic assay, combined with the active-site titration approach of Ackermann and Potter, revealed that both M. tuberculosis enzymes had very low k cat values. One possible explanation for the low catalytic activity of M. tuberculosis ThyX is that its true biological substrates remain to be identified. Alternatively, this slow-growing pathogen, with low demands for TMP, may have evolved to down-regulate TS activities by altering the turnover rate of individual enzyme molecules, perhaps to preserve total protein quantities for other purposes. In many organisms, TS is often used as a part of larger complexes of macromolecules that control replication and DNA repair.Conclusions/Significance
Thus, the present enzymatic characterization of ThyA and ThyX from M. tuberculosis provides a framework for future development of cell-active inhibitors and the biological roles of these TS enzymes in M. tuberculosis. 相似文献6.
《Autophagy》2013,9(10):1523-1525
Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We report that physiological concentrations of 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits M. tuberculosis and HIV replication in co-infected macrophages through human cathelicidin microbial peptide-dependent autophagy that requires phagosomal maturation. These findings provide a biological explanation for the importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections. 相似文献
7.
A Dual Read-Out Assay to Evaluate the Potency of Compounds Active against Mycobacterium tuberculosis
Juliane Ollinger Mai Ann Bailey Garrett C. Moraski Allen Casey Stephanie Florio Torey Alling Marvin J. Miller Tanya Parish 《PloS one》2013,8(4)
Tuberculosis is a serious global health problem caused by the bacterium Mycobacterium tuberculosis. There is an urgent need for discovery and development of new treatments, but this can only be accomplished through rapid and reproducible M. tuberculosis assays designed to identify potent inhibitors. We developed an automated 96-well assay utilizing a recombinant strain of M. tuberculosis expressing a far-red fluorescent reporter to determine the activity of novel compounds; this allowed us to measure growth by monitoring both optical density and fluorescence. We determined that optical density and fluorescence were correlated with cell number during logarithmic phase growth. Fluorescence was stably maintained without antibiotic selection over 5 days, during which time cells remained actively growing. We optimized parameters for the assay, with the final format being 5 days’ growth in 96-well plates in the presence of 2% w/v DMSO. We confirmed reproducibility using rifampicin and other antibiotics. The dual detection method allows for a reproducible calculation of the minimum inhibitory concentration (MIC), at the same time detecting artefacts such as fluorescence quenching or compound precipitation. We used our assay to confirm anti-tubercular activity and establish the structure activity relationship (SAR) around the imidazo[1,2-a]pyridine-3-carboxamides, a promising series of M. tuberculosis inhibitors. 相似文献
8.
Nidhi Jatana Sarvesh Jangid Garima Khare Anil K. Tyagi Narayanan Latha 《Journal of molecular modeling》2011,17(2):301-313
Tuberculosis (TB) is a global health problem and the situation has become more precarious due to the advent of HIV infections
and continuous rise in the number of multi-drug resistant strains of Mycobacterium tuberculosis (M. tb). Biochemical studies on Fatty Acyl-CoA Synthetases (FadD13), one of the gene products of mymA operon, have provided insights
into the involvement of this protein in the activation of fatty acids. Due to non-availability of the crystal structure of
FadD13, we have employed in silico approaches to resolve and characterize the structure of this important protein of M. tb. A three dimensional model of M. tb FadD13 was predicted by a de novo structure prediction server that integrates fragment assembly with SimFold energy function.
With the aid of molecular mechanics and dynamics methods, the final model was obtained and assessed subsequently for global
and local accuracy by various assessment programs. With this model, a flexible docking study with the substrates was performed.
Results of ligand interactions with key amino acids in the binding site are also summarized. The molecular model for the M. tb FadD13 obtained sheds light on the topographical features of the binding pocket of the protein and provides atomic insight
into the possible modes of substrate recognition. The three-dimensional model of FadD13 presented here would be helpful in
guiding both enzymatic studies as well as design of specific inhibitors. 相似文献
9.
Identification of aminopyrimidine‐sulfonamides as potent modulators of Wag31‐mediated cell elongation in mycobacteria
下载免费PDF全文
![点击此处可从《Molecular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
János Pató Gaëlle S. Kolly Jana Korduláková Martin Forbak Joanna C. Evans Rita Székely Jan Rybniker Zuzana Palčeková Júlia Zemanová Isabella Santi François Signorino‐Gelo Liliana Rodrigues Anthony Vocat Adrian S. Covarrubias Monica G. Rengifo Kai Johnsson Sherry Mowbray Joseph Buechler Vincent Delorme Priscille Brodin Graham W. Knott José A. Aínsa Digby F. Warner Katarína Mikušová John D. McKinney Ruben C. Hartkoorn 《Molecular microbiology》2017,103(1):13-25
10.
《Bioorganic & medicinal chemistry》2020,28(13):115579
In this study, we screen three heterocyclic structures as potential inhibitors of UDP-galactopyranose mutase (UGM), an enzyme involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis. In order to understand the binding mode, docking simulations are performed on the best inhibitors. Their activity on Mycobacterium tuberculosis is also evaluated. This study made it possible to highlight an “oxazepino-indole” structure as a new inhibitor of UGM and of M. tuberculosis growth in vitro. 相似文献
11.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):259-263
AbstractIn a quest for developing novel anti-tubercular agents, a series of 3-benzylidene-4-chromanones 1a–l were evaluated for growth inhibition of Mycobacterium tuberculosis H37Rv. Three promising compounds 1d, g, j emerged as the lead compounds with the IC50 and IC90 values of less than 1?µg/mL. Evaluation of the potent compounds 1d, g, j and k against Vero monkey kidney cells revealed that these compounds are far more toxic to M. tuberculosis than to Vero cells. Structure–activity relationships demonstrated that 3-benzylidene-4-chromanones are more potent against M. tuberculosis than the related 2-benzylidene cycloalkanones and the meta substituted chromanone derivatives are more active than their ortho- and para-counterparts. Some guidelines for amplifying the project are presented. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2019,29(13):1665-1672
Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB) virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis – actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease – which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria. 相似文献
13.
Ian M. Bassett Shichun Lun William R. Bishai Haidan Guo Joanna R. Kirman Mudassar Altaf Ronan F. O’Toole 《Journal of microbiology (Seoul, Korea)》2013,51(5):651-658
Many whole cell screens of chemical libraries currently in use are based on inhibition of bacterial growth. The goal of this study was to develop a chemical library screening model that enabled detection of compounds that are active against drug-tolerant non-growing cultures of Mycobacterium tuberculosis. An in vitro model of low metabolically active mycobacteria was established with 8 and 30 day old cultures of M. smegmatis and M. tuberculosis, respectively. Reduction of resazurin was used as a measure of viability and the assay was applied in screens of chemical libraries for bactericidal compounds. The model provided cells that were phenotypically-resilient to killing by first and second-line clinical drugs including rifampicin. Screening against chemical libraries identified proteasome inhibitors, NSC310551 and NSC321206, and a structurally-related series of thiosemicarbazones, as having potent killing activity towards aged cultures. The inhibitors were confirmed as active against virulent M. tuberculosis strains including multi- and extensively-drug resistant clinical isolates. Our library screen enabled detection of compounds with a potent level of bactericidal activity towards phenotypically drug-tolerant cultures of M. tuberculosis. 相似文献
14.
《Molecular membrane biology》2013,30(2):217-227
AbstractThe increasing number of multidrug-resistant pathogenic microorganisms is a serious public health issue. Among the multitude of mechanisms that lead to multidrug resistance, the active extrusion of toxic compounds, mediated by MDR efflux pumps, plays an important role. In our study we analyzed the inhibitory capability of 26 synthesized zosuquidar derivatives on three ABC-type MDR efflux pumps, namely Saccharomyces cerevisiae Pdr5 as well as Lactococcus lactis LmrA and LmrCD. For Pdr5, five compounds could be identified that inhibited rhodamine 6G transport more efficiently than zosuquidar. One of these is a compound with a new catechol acetal structure that might represent a new lead compound. Furthermore, the determination of IC50 values for rhodamine 6G transport of Pdr5 with representative compounds reveals values between 0.3 and 0.9 μM. Thus the identified compounds are among the most potent inhibitors known for Pdr5. For the ABC-type efflux pumps LmrA and LmrCD from L. lactis, seven and three compounds, which inhibit the transport activity more than the lead compound zosuquidar, were found. Interestingly, transport inhibition for LmrCD was very specific, with a drastic reduction by one compound while its diastereomers showed hardly an effect. Thus, the present study reveals new potent inhibitors for the ABC-type MDR efflux pumps studied with the inhibitors of Pdr5 and LmrCD being of particular interest as these proteins are well known model systems for their homologs in pathogenic fungi and Gram-positive bacteria. 相似文献
15.
Christian Dupont Albertus Viljoen Faustine Dubar Mickaël Blaise Audrey Bernut Alexandre Pawlik Christiane Bouchier Roland Brosch Yann Guérardel Joël Lelièvre Lluis Ballell Jean‐Louis Herrmann Christophe Biot Laurent Kremer 《Molecular microbiology》2016,101(3):515-529
The natural resistance of Mycobacterium abscessus to most commonly available antibiotics seriously limits chemotherapeutic treatment options, which is particularly challenging for cystic fibrosis patients infected with this rapid‐growing mycobacterium. New drugs with novel molecular targets are urgently needed against this emerging pathogen. However, the discovery of such new chemotypes has not been appropriately performed. Here, we demonstrate the utility of a phenotypic screen for bactericidal compounds against M. abscessus using a library of compounds previously validated for activity against M. tuberculosis. We identified a new piperidinol‐based molecule, PIPD1, exhibiting potent activity against clinical M. abscessus strains in vitro and in infected macrophages. Treatment of infected zebrafish with PIPD1 correlated with increased embryo survival and decreased bacterial burden. Whole genome analysis of M. abscessus strains resistant to PIPD1 identified several mutations in MAB_4508, encoding a protein homologous to MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis was unaffected, PIPD1 strongly inhibited the transport of trehalose monomycolate, thereby abrogating mycolylation of arabinogalactan. Mapping the mutations conferring resistance to PIPD1 on a MAB_4508 tridimensional homology model defined a potential PIPD1‐binding pocket. Our data emphasize a yet unexploited chemical structure class against M. abscessus infections with promising translational development possibilities. 相似文献
16.
Ashish K. Pathak Vibha Pathak Joseph A. Maddry William J. Suling Sudagar S. Gurcha Gurdyal S. Besra Robert C. Reynolds 《Bioorganic & medicinal chemistry》2001,9(12):2217
The appearance multi-drug resistant Mycobacterium tuberculosis (MTB) throughout the world has prompted a search for new, safer and more active agents against tuberculosis. Based on studies of the biosynthesis of mycobacterial cell wall polysaccharides, octyl 5-O-(α-
-arabinofuranosyl)-α-
-arabinofuranoside analogues were synthesized and evaluated as inhibitors for M. tuberculosis and Mycobacterium avium. A cell free assay system has been used for the evaluation of these disaccharides as substrates for mycobacterial arabinosyltransferase activity. 相似文献
17.
M. Chaitanya B. Babajan C. M. Anuradha M. Naveen C. Rajasekhar P. Madhusudana Chitta Suresh Kumar 《Journal of molecular modeling》2010,16(8):1357-1367
Tuberculosis (TB) is still a major public health problem, compounded by the human immunodeficiency virus (HIV)-TB co-infection
and recent emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR)-TB. In this context, aspartokinase
of mycobacterium tuberculosis has drawn attention for designing novel anti-TB drugs. Asp kinase is an enzyme responsible for the synthesis of 4-phospho-L-aspartate from L-aspartate and involved in
the branched biosynthetic pathway leading to the synthesis of amino acids lysine, threonine, methionine and isoleucine. An
intermediate of lysine biosynthetic branch, mesodiaminopimelate is also a component of the peptidoglycan which is a component
of bacterial cell wall. To interfere with the production of all these amino acids and cell wall, it is possible to inhibit
Asp kinase activity. This can be achieved using Asp kinase inhibitors. In order to design novel Asp kinase inhibitors as effective
anti-TB drugs, it is necessary to have an understanding of the binding sites of Asp kinase. As no crystal structure of the enzyme
has yet been published, we built a homology model of Asp kinase using the crystallized Asp kinase from M. Jannaschii, as template structures (2HMF and 3C1M). After the molecular dynamics refinement, the optimized homology model was assessed
as a reliable structure by PROCHECK, ERRAT, WHAT-IF, PROSA2003 and VERIFY-3D. The results of molecular docking studies with
natural substrates, products and feedback inhibitors are in agreement with the published data and showed that ACT domain plays
an important role in binding to ligands. Based on the docking conformations, pharmacophore model can be developed by probing
the common features of ligands. By analyzing the results, ACT domain architecture, certain key residues that are responsible
for binding to feedback inhibitors and natural substrates were identified. This would be very helpful in understanding the
blockade mechanism of Asp kinase and providing insights into rational design of novel Asp kinase inhibitors for M.tuberculosis. 相似文献
18.
Katharina Brunner Eva Maria Steiner Rudraraju Srilakshmi Reshma Dharmarajan Sriram Robert Schnell Gunter Schneider 《Bioorganic & medicinal chemistry letters》2017,27(19):4582-4587
CysK1 and CysK2 are two members of the cysteine/S-sulfocysteine synthase family in Mycobacterium tuberculosis, responsible for the de novo biosynthesis of l-cysteine, which is subsequently used as a building block for mycothiol. This metabolite is the first line defense of this pathogen against reactive oxygen and nitrogen species released by host macrophages after phagocytosis. In a previous medicinal chemistry campaign we had developed urea-based inhibitors of the cysteine synthase CysM with bactericidal activity against dormant M. tuberculosis. In this study we extended these efforts by examination of the in vitro activities of a library consisting of 71 urea compounds against CysK1 and CysK2. Binding was established by fluorescence spectroscopy and inhibition by enzyme assays. Several of the compounds inhibited these two cysteine synthases, with the most potent inhibitor displaying an IC50 value of 2.5 µM for CysK1 and 6.6 µM for CysK2, respectively. Four of the identified molecules targeting CysK1 and CysK2 were also among the top ten inhibitors of CysM, suggesting that potent compounds could be developed with activity against all three enzymes. 相似文献
19.
Auradee Punkvang Supa Hannongbua Patchreenart Saparpakorn Pornpan Pungpo 《Journal of biomolecular structure & dynamics》2016,34(5):1079-1091
The Mycobacterium tuberculosis protein kinase B (PknB) is critical for growth and survival of M. tuberculosis within the host. The series of aminopyrimidine derivatives show impressive activity against PknB (IC50 < .5 μM). However, most of them show weak or no cellular activity against M. tuberculosis (MIC > 63 μM). Consequently, the key structural features related to activity against of both PknB and M. tuberculosis need to be investigated. Here, two- and three-dimensional quantitative structure–activity relationship (2D and 3D QSAR) analyses combined with molecular dynamics (MD) simulations were employed with the aim to evaluate these key structural features of aminopyrimidine derivatives. Hologram quantitative structure–activity relationship (HQSAR) and CoMSIA models constructed from IC50 and MIC values of aminopyrimidine compounds could establish the structural requirements for better activity against of both PknB and M. tuberculosis. The NH linker and the R1 substituent of the template compound are not only crucial for the biological activity against PknB but also for the biological activity against M. tuberculosis. Moreover, the results obtained from MD simulations show that these moieties are the key fragments for binding of aminopyrimidine compounds in PknB. The combination of QSAR analysis and MD simulations helps us to provide a structural concept that could guide future design of PknB inhibitors with improved potency against both the purified enzyme and whole M. tuberculosis cells. 相似文献