🔬 Med Chem of Antidiabetics
Structure:
A and B chain connected with disulfide bonds
🔗 (A7-B6, A20-B19)
A chain - 21 aa
B chain 30 aa
Oligomeric Insulin
- Monomer
⭐ Insulin only binds in monomeric form
- Higher oligomer
NO activity
[monomer] > 100 nM
[monomer] < 100 nM
Dimer
Insulin likes to dimerize
Hexamer
3 dimers combine in presence of Zn2+
Stability
- Unfolding/Denaturization of Insulin
- Heat
- Shear forces
- Hydrophobic surfaces
Prevent denaturation:
✅ Proper storage (4'C)
Prolonged storage ( > 4 mos)
-> Deamidation of Asn (A21)*
-- 1-2%
-- 25'C, 6 mos: 90%
Most soluble so shortest onset, DOA
Deamidation of Asn residues
-- EXCEPT Asn (B3)
Asn (B3) deamidation gives aspartate and isoaspartate
-- active modified insulins
Absorption
Depends on concentration and form of insulin
⬆ [insulin]
-- more polymeric (less soluble)
-- lower absorption
Human insulin vs. Non-human insulin
Different residues in non-human, modified insulin
If residues are not important for activity, non-human insulin can still be used
SARs
- ⬇ Activity
-- Removal of 8 residues from C-terminus of B chain destroys activity
-- Removal of N-Gly from A chain **diminishes activity
Mutations to arginine change activity
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INSULIN
✒
ORAL ANTIDIABETICS
💊
a-Glucosidase Inhibitors
Biguanides
Thiazolidinediones
DPP-4 Inhibitors (-gliptins)
Sulfonylureas
Core Structure
⭐ Sulfonyl group
⭐ Urea group
Antibiotics
-- have a sulfonyl but no urea
-- amine at C-4 (inflammation)
R, R' groups can be alkyl chains or aromatic rings
Antibiotics mimic precursor of folic acid, PABA
Core Structure
⭐ Two guanides
Core Structure
Core Structure
Core Structure
MOA: directly interacts with v-ATPase and activates ATPK
SAR with recently discovered MOA is unclear
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💡 Critical SAR studied from PPAR-y binding to pioglitazone
⭐ Transition state (of sugar hydrolysis) mimic
-- transition state competitive inhibitor
Substitution of O to N
Substitution of C to N
💡 Critical SAR studied from
a-glucosidase binding to acarbose
DPP-4 MOA
DPP-4 deactivates incretin by removing first 2 residues
⭐ Mimic of the 2 aa residues that are removed by DPP-4
💡 Critical SAR studied from DPP-4 binding to sitagliptin
⭐ Prefers proline at P1 site
⭐ NH2 at P2 site
Cyanopyrrolidine PI
-- potent due to transient covalent trapping of nitrile group by the active site Ser360
(slow tight-binding kinetics of reversible cov bonds)
DPP-4 can also bind to CD26 (T cell activation marker), causing immunological effect
Bovine insulin has 3 different residues from hIn
Porcine insulin has 1 different residue from hIn