Lead to drugs Flashcards
What is a pyridine type nitrogen?
A benzene core in which one -CH group is replaced by a N atom. Also Next to a double bond.
What is a pyrrole type nitrogen?
Pyrrole, any of a class of organic compounds of the heterocyclic series characterized by a ring structure composed of four carbon atoms andone N atom. The simplest member of the pyrrole family is pyrrole itself, a compound with molecular formula C4H5N.
Which is more basic pyrrole or pyridine type nitrogen?
Pyridine consists of a stable conjugated system of 3 double bonds in the aromatic ring. Hence, the lone pair of electrons present on the nitrogen atom in pyridine has the ability to donate a hydrogen ion easily or a Lewis acid. Thus, pyridine is a stronger base than pyrrole.
Pyrrole, any of a class of organic compounds of the heterocyclic series characterized by a ring structure composed of four carbon atoms and one nitrogen atom.
What types of bonding are involved in drug-receptor interactions?
- Covalent bonds
- Ionic bonds
- Hydrogen bonds
- Hydrophobic or Van der Waal Forces
What are things to note about covalent bonds?
- Rarely seen in pharmacodynamic receptors.
- Lead to receptor block through irreversible bonding.
- Important in Drug-DNA interactions eg Alkyl halides.
- Very Strong - 40-110 kcal/mol
What are some amino acids that interact with covalent bonds?
- Cysteine (has SH so can form )
- Serine
When can disulphide (bridges) bonds form?
It can only happen between thiols so SH to SH.
Sulphur on its own/next to carbons can’t form it.
What are things to note about ionic bonds?
- Important in drug-receptor interactions.
- Allow the drug to bind but also to dissociate.
- Mutual attraction between the receptor and drug based on opposing charges.
- Medium strength - 5-10 kcal/mol
- Occurs between acids and bases.
What are the amino acids that interact with ionic bonds?
- Glutamic acid
- Lysine (primary amine)
- Arginine (Guanine type base)
- Histidine (pyridine type nitrogen)
- Aspartic acid
What are things to note about hydrogen bonds?
- Essential in drug-receptor interactions.
- Dipole interactions.
- Exchange oxygen for sulphur - weaken drug interactions.
- Important to be additive - too weak alone - 2-5 kcal/mol.
What amino acids interact with hydrogen bonds?
- Serine
- Threonine
- Cysteine
- Tyrosine
- Aspartamine
- Glutamine
- Histidine
- Tryptophan
What are things to note about hydrophobic or Van der Waals forces?
- Occurs w/ neutral hydrocarbons.
- Fluxional changes in electron distribution - temporary interaction of dipoles.
- Require considerable complementarily.
- Aromatic residues - pi-pi interactions between faces.
- Alkyl residues - fit into hydrophobic pockets formed by aromatic residues.
What amino acids interact with hydrophobic or Van der Waals forces?
- Glycine
- Alanine
- Valine
- Leucine
- Isoleucine
- Phenylalanine
- Proline
- Methionine (can’t disulphide bridge)
Which amino acids overlap in the interactions?
- Cysteine & serine –> In both covalent and H-bonds.
- Histidine –> Ionic and H-bonds
Why might an ionic bond (electrostatic)?
Receptor may have an acid near the binding site. Protonated will interact with acid as its negative.
What can form H-bonds?
Lone pairs eg OH, COOH
Which type of nitrogen is basic?
Pyridine
What does Huckel’s rule mean?
if a cyclic, planar molecule has 4n+2 π electrons, it is considered aromatic
When do Van der Waals interactions happen?
Btwn induced dipole and induced dipole.
Very weal
Contribute to binding
How is Structure-Activity relationships (SAR) studies?
Synthesis of analogues.
What things can you do to study SAR?
Chemical modification of groups in lead structure.
Alternative - synthesis of full structure.
What sort of modifications could be done to study SAR?
Steric Effects
Aromatic substitution
Extension of the structure
Ring variations
Ring fusions
Isosteres
Simplification of the structure
Rigidification of the structure
Conformation blockers (Stop free rotation)
What can alcohol do?
Changes H-bonding and steric effect.
Change to an ester.
Alcohol can fit in binding site and H-bonds but when it becomes an ester it no longer fits.
What does an amine do?
Change a primary or secondary amine to amide.
Changes H-bonding, pKa (no longer basic) and steric effects.
(possible to covert tertiary amine to secondary (changes steric effect but not pKa))
