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Identification of novel scaffolds for Monoamine oxidase B inhibitors

Odhar, Hasanain
http://rave.ohiolink.edu/etdc/view?acc_num=kent1394416913

Abstract Details

2014, MS, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Parkinsonism is a progressive neurodegenerative disease that mainly affects elderly people. The disease is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. This gradual loss of dopaminergic neurons will result in the appearance of four motor related symptoms and these are: tremor, bradykinesia, rigidity and postural imbalance. Current therapeutic approach focuses mainly on symptoms attenuation through dopamine replacement therapy. In this regard, recent drug design approaches are focused mainly on the production of multi targeted drug molecules as an attempt to generate a medication that is capable of halting or slowing down the progression of the degenerative process. Such goal can be achieved through the employment of designed multiple ligands (DMLs) strategy. MAO-B enzyme appears to be a promising target for such drug discovery approach. For our project, twenty four chemical compounds were selected (based on similarity analysis) as possible candidates for MAO-B inhibition. Structure-based virtual screening techniques (docking programs) were used to build an early impression about the binding tendency of these compounds to MAO-B crystal and bovine serum albumin (BSA) crystal. These compounds were then evaluated in vitro for their potentials to inhibit MAO isozymes and to quench peroxyl radicals. The pharmacokinetic profile for these compounds was investigated through the application of bovine serum albumin (BSA) binding assay and parallel artificial membrane permeability assay (PAMPA). Finally, a basic structure-activity relationship (SAR) study was established by comparing the structure, activity and docking images for compounds with related building blocks. As a conclusion to our SAR study, we believe that the 2-thioxo-1, 3-thiazolidin-4-one ring is essential for both MAO-B inhibition potential and radical quenching capacity. We also believe that 8-hydroxyquinoline moiety is essential for radical quenching activity; previous researches have shown that 8-hydroxyquinoline molecule can also act as a strong iron chelator. By combining 2-thioxo-1, 3-thiazolidin-4-one ring with 8-hydroxyquinoline moiety, we were able to generate two hypothetical scaffolds (scaffolds A and B). We believe that the attachment of L-alanine moiety to our design (scaffolds A and B) will enhance the selective delivery of these scaffolds into the brain. The addition of L-alanine will result in the generation of two additional scaffolds (E and F); these new scaffolds can act as good substrates to the large neutral amino acid transporter in the blood brain barrier. We believe that these scaffolds can be used for the development of a potent, selective and centrally acting MAO-B inhibitor with a possible radical quenching capacity and a promising iron chelating activity.
Werner Geldenhuys, Ph.D. (Advisor)
Altaf Darvesh, Ph.D. (Committee Member)
Richard Carroll, Ph.D. (Committee Member)
162 p.
Biomedical Research; Neurosciences; Pharmaceuticals; Pharmacology; Pharmacy Sciences
Parkinsonism; Monoamine oxidase; Scaffold; High throughput screening; Drug design; structure-activity relationship study; Thiazolidine; 8-hydroxyquinoline; L-alanine

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Citations

  • Odhar, H. (2014). Identification of novel scaffolds for Monoamine oxidase B inhibitors [Master's thesis, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1394416913

    APA Style (7th edition)

  • Odhar, Hasanain. Identification of novel scaffolds for Monoamine oxidase B inhibitors. 2014. Kent State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1394416913.

    MLA Style (8th edition)

  • Odhar, Hasanain. "Identification of novel scaffolds for Monoamine oxidase B inhibitors." Master's thesis, Kent State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1394416913

    Chicago Manual of Style (17th edition)

kent1394416913
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This open access ETD is published by Kent State University and OhioLINK.