This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Chemical Genetics - Small Molecule Interactions
PubChem
The PubChem is comprised of three linked databases - PubChem Compound, PubChem Subtance and PubChem Bioassay. Many proteins in biological system have specific binding sites for small molecules [3]. Knowledge of these binding activity (protein-small molecule interactions) is critical to understand how proteins function. Besides, most drugs are small molecules. These small molecules could be identified by entering "hexosaminidase A" (HEXA) in the Entrez database. One bioassay was shown to be related to HEXA in the PubChem Bioassay search engine: Inhibition of human placental lysosomal hexosaminidase Aat 5 uM. Three compounds were identified in this bioassays.
The compounds below are from bioassay AID: 515850
Molecule 1: CHEMBL1253585
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Compound ID: 52949691 Molecular Weight: 266.15312 [g/mol] Molecular Formula: C8H13NO4Se H-Bond Donor: 3 H-Bond Acceptor: 5 |
Compound ID: 52948755 Molecular Weight: 337.32786 [g/mol] Molecular Formula: C15H19N3O6 XLogP3-AA: 0.1 _ H-Bond Donor: 4 H-Bond Acceptor: 7 |
Analysis
One of the bioassay results from Molecule 3 - NGT shows that activation of beta Hex A alpha G269S/c.1278insTACT mutant isolated from Tay-Sachs disease patient assessed as increase in HEX A activity at 300 ug/ml relative to control (AID: 356778). According to Maegawa GH et al., pyrimethamine (PYR (2,4-diamino 5-(4-chlorophenyl)-6-ethylpyrimidine)) can function as a mutation-specific pharmacological chaperones, in which stabilizing the conformation of a mutant HEXA and increasing protein lysosomal Hex A levels.
References
1. PubChem
2. Entrez
3. Accordino, S. , Morini, M. , Belén Sierra, M. , Ariel Rodríguez Fris, J. , Appignanesi, G. , et al. (2012). Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces. Proteins. doi: 10.1002/prot.24069
4. Platt, F. , Neises, G. , Reinkensmeier, G. , Townsend, M. , Perry, V. , et al. (1997). Prevention of lysosomal storage in tay-sachs mice treated with n-butyldeoxynojirimycin. Science (Washington D C), 276(5311), 428-431. [PUBMED]
1. PubChem
2. Entrez
3. Accordino, S. , Morini, M. , Belén Sierra, M. , Ariel Rodríguez Fris, J. , Appignanesi, G. , et al. (2012). Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces. Proteins. doi: 10.1002/prot.24069
4. Platt, F. , Neises, G. , Reinkensmeier, G. , Townsend, M. , Perry, V. , et al. (1997). Prevention of lysosomal storage in tay-sachs mice treated with n-butyldeoxynojirimycin. Science (Washington D C), 276(5311), 428-431. [PUBMED]