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The Dual-Targeting Activity of the Metabolite Substrate of Para-amino Salicyclic Acid in the Mycobacterial Folate Pathway: Atomistic and Structural Perspectives
- Source :
- The Protein Journal. 39:106-117
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Therapeutic targeting of folate biosynthetic pathway has recently been explored as a viable strategy in the treatment of tuberculosis. The bioactive metabolite substrate of Para-amino salicyclic acid (PAS-M) reportedly dual-targets dihydrofolate reductase (DHFR) and flavin-dependent thymidylate synthase (FDTS), two essential enzymes in folate biosynthetic pathway. However, the molecular mechanisms and structural dynamics of this dual inhibitory activity of the PAS-M remain elusive. Molecular dynamics simulations revealed that binding of PAS-M towards DHFR is characterized by a recurrence of strong conventional hydrogen bond interactions between a peculiar DHFR binding site residue (Asp27) and the 2-amino-decahydropteridin-4-ol group of PAS-M. Similarly, the binding of PAS-M towards FDTS also involved consistent strong conventional hydrogen bond interactions between some specific residues (Tyr101, Arg172, Thr4, Gln103, Arg87 and Gln106) and, the 2-amino-decahydropteridin-4-ol group, thus establishing the cruciality of the group. Structural dynamics of the bound complexes of both enzymes revealed that, upon binding, PAS-M is anchored at the entrance of hydrophobic pockets by strong hydrogen bond interactions while the rest of the structure gains access to deeper hydrophobic residues to engage in favorable interactions. Further analysis of atomistic changes of both enzymes showed increased C-α atom deviations as well as an increase C-α atoms radius of gyration consistent with structural disorientations. These conformational changes possibly interfered with the biological functions of the enzymes and hence their inhibition as experimentally reported. Structural Insights provided could open up a novel paradigm of structure-based design of multi-targeting inhibitors of biological targets in the folate biosynthetic pathway toward tuberculosis therapy.
- Subjects :
- Models, Molecular
Stereochemistry
Metabolite
Antitubercular Agents
Molecular Conformation
Bioengineering
Biochemistry
Analytical Chemistry
03 medical and health sciences
chemistry.chemical_compound
Residue (chemistry)
Molecular dynamics
Folic Acid
Dihydrofolate reductase
Bioorganic chemistry
Binding site
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
biology
Hydrogen bond
030302 biochemistry & molecular biology
Organic Chemistry
Mycobacterium tuberculosis
Thymidylate Synthase
Aminosalicylic Acid
Tetrahydrofolate Dehydrogenase
Enzyme
chemistry
Drug Design
biology.protein
Folic Acid Antagonists
Subjects
Details
- ISSN :
- 18758355 and 15723887
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- The Protein Journal
- Accession number :
- edsair.doi.dedup.....5d4bdb906eea684de545aa764694abd5