scholarly journals Arabinosyl transferase inhibitor design against Mycobacterium tuberculosis using ligand based drug design approach

2014 ◽  
Vol 9 (2) ◽  
Author(s):  
Bhaskor Kolita ◽  
Dhrubajyoti Gogoi ◽  
Partha Pratim Dutta ◽  
Manobjyoti Bordoloi ◽  
Rajib Lochan Bezbaruah
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Design Approach ◽  
Inhibitor Design

Design, synthesis and evaluation of diphenyl ether analogues as antitubercular agents

RSC Advances ◽  
2016 ◽  
Vol 6 (112) ◽  
pp. 110571-110582 ◽  
Author(s):  
Bharathkumar Inturi ◽  
Gurubasavaraj V. Pujar ◽  
Madhusudhan N. Purohit ◽  
Viswanathan B. Iyer ◽  
Sowmya G. S. ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Acyl Carrier Protein ◽  
Diphenyl Ether ◽  
Design Approach ◽  
Carrier Protein ◽  
Antitubercular Agents ◽  
Structure Based Drug Design ◽  
Design Synthesis ◽  
Diphenyl Ethers

We herein report the investigation of new diphenyl ethers asMycobacterium tuberculosisenoyl-acyl carrier protein reductase (InhA) inhibitors by structure-based drug design approach.

scholarly journals Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Jérémie Piton ◽  
Anthony Vocat ◽  
Andréanne Lupien ◽  
Caroline S. Foo ◽  
Olga Riabova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Antitubercular Activity ◽  
Cysteine Residue ◽  
Drug Candidate ◽  
Structure Based Drug Design ◽  
Content Type ◽  
Active Site Cysteine ◽  
Covalent Adducts

ABSTRACT Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

scholarly journals Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach

2017 ◽  
Vol 174 (14) ◽  
pp. 2209-2224 ◽  
Author(s):  
Ali Ryan ◽  
Elena Polycarpou ◽  
Nathan A Lack ◽  
Dimitrios Evangelopoulos ◽  
Christian Sieg ◽  
...  
Keyword(s):  
Drug Design ◽  
Design Approach ◽  
Novel Target

scholarly journals Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Changyao Li ◽  
Yan Chai ◽  
Hao Song ◽  
Changjiang Weng ◽  
Jianxun Qi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mycobacterium Tuberculosis ◽  
High Resolution ◽  
Drug Design ◽  
Active Site ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Fever Virus ◽  
Potential Drug ◽  
Content Type

ABSTRACT E165R, a highly specific dUTP nucleotidohydrolase (dUTPase) encoded by the African swine fever virus (ASFV) genome, is required for productive replication of ASFV in swine macrophages. Here, we solved the high-resolution crystal structures of E165R in its apo state and in complex with its product dUMP. Structural analysis explicitly defined the architecture of the active site of the enzyme as well as the interaction between the active site and the dUMP ligand. By comparing the ASFV E165R structure with dUTPase structures from other species, we found that the active site of E165R is highly similar to those of dUTPases from Mycobacterium tuberculosis and Plasmodium falciparum, against which small-molecule chemicals have been developed, which could be the potential drug or lead compound candidates for ASFV. Our results provide important basis for anti-ASFV drug design by targeting E165R. IMPORTANCE African swine fever virus (ASFV), an Asfivirus affecting pigs and wild boars with up to 100% case fatality rate, is currently rampaging throughout China and some other countries in Asia. There is an urgent need to develop therapeutic and preventive reagents against the virus. Our crystallographic and biochemical studies reveal that ASFV E165R is a member of trimeric dUTP nucleotidohydrolase (dUTPase) family that catalyzes the hydrolysis of dUTP into dUMP. Our apo-E165R and E165R-dUMP structures reveal the constitutive residues and the configuration of the active center of this enzyme in rich detail and give evidence that the active center of E165R is very similar to that of dUTPases from Plasmodium falciparum and Mycobacterium tuberculosis, which have already been used as targets for designing drugs. Therefore, our high-resolution structures of E165R provide useful structural information for chemotherapeutic drug design.

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