Introduction Flashcards
4 steps of drug design chain
- Select biochemical target.
- Find small molecule that will bind to and alter activity of target.
- Optimize lead for selectivity and binding affinity.
- Discover molecule for human clinical trials.
Drug
A molecule that interacts with a target biological molecule triggering a therapeutically desired physiological effect.
Target identification
Identifying a biomolecule that may be associated with a disease process.
Target validation
determination that a biomolecular target is critically involved in a disease process and a potentially valuable point of intervention for new drugs.
Hit
A compound that exhibits activity in a relevant biochemical assay; may become a lead.
Lead
A compound that can serve as a template for the synthesis of a series of related compounds with sufficient potential to be optimized and then developed into a drug.
Lead Optimization
The modification of a Lead synthetically to satisfy a variety of properties required for clinical efficacy.
In the ______ ______ step, structure based drug discovery depends obtaining the target’s _______ _______ by ___ or __________ __________, followed by —(1)—- or —(2)—.
Lead finding, protein structure, NMR, X-ray crystallography, (1) virtual screening, (2) computer-guided lead optimization and synthesis.
Alternative to structure based design and discovery
Experimental screening of compound collections via high throughput screening (HTS)
PNP function
Purine Nucleoside Phosphorylase- salvages purine bases by adding inorganic phosphate to a nucleoside to produce a ribose monophosphate and free purine base (2 rings).
INO —> Hx
GUO —> Gua
Role of PNP in human disease
Children with deficiency in the gene for PNP show severe T-cell immunodeficiency.
dGUO buildup in proliferating T cells —> dGMP by deoxycytidine kinase —> dGTP —> Inhibition of Ribonucleotide Reductase and thus Inhibition of DNA Synthesis.
TP function
Thymidine Phosphorylase (aka Platelet Derived Endothelial Growth Factor)- promotes phosphorlysis of thymidine into deoxyribose monophosphate, which promotes angiogenesis and thymine base.
Role of TP in human disease
TP is known to be expressed at high levels in a number of solid tumors and cellular levels of TP correlate well with the
invasiveness and aggressiveness of a number of human
cancers (e.g., colon, breast, bladder, ovarian, etc.).
PyNP significance
Pyridine Nucleoside Phosphorylase- homologous to human TP crystallized B.
Stearothermophilus, also converts uridine to uracil.
PyNP structure
Has open and closed form. Each subunit has two domains (alpha and alpha/beta connected by loops that form a hinge).
