M5 Optimizing a Lead

Hits are tested in a bioassay, and those that show activity become leads.
Leads must be optimized to increase their likelihood of becoming drugs.
Lead optimization is an iterative process involving medicinal chemistry.
Medicinal chemistry analyzes the lead molecule's structure and how alterations can improve efficacy.

If an aromatic ring (R group) on a lead molecule is oriented into the solution (not involved in binding), altering its structure won't affect potency.
If the aromatic ring is oriented into the active/binding site, any alteration of the R group will alter its potency.
Example:
- Substituting R with different groups changes the inhibitory concentration (IC50).
  - Methoxy, methyl, chloro, fluoro, cyanide, $O_2$
- Replacing R with $NO_2$ results in an IC50 of 2 nanomolar, which is desirable in drug discovery.
- Lower concentration of lead compound needed for activity = better chance of becoming a good drug.
Substitution with electron-donating groups (less electronegative atoms) will not increase potency.
Substitution with electron-withdrawing groups (most electronegative atoms like chlorine, oxygen) will increase potency.

Increasing the hydrophobic nature of the R group can increase potency if it's within the binding cavity.
Examples:
- Increasing hydrophobicity with hydrogen, methyl, ethyl, and isopropyl groups increases potency within the binding site's confines.
- Tertiary butyl and phenol groups expand beyond the binding site, increasing steric effects and decreasing potency.
- Hydrophobicity should be increased within the confine of the binding site.

Orientation of hydrogen bond donors/acceptors on the lead molecule significantly affects potency.
Correct orientation:
- Adding an amine or piperidine in the meta position allows for perfect orientation of the hydrogen bond donor towards the hydrogen bond acceptor at the binding site.
Incorrect orientation:
- Changing the location to the ortho position misaligns the hydrogen bond donor, preventing hydrogen bond formation and worsening potency.

Chirality: a molecule with four different groups bound to a central atom.
Mirror images are called enantiomers and cannot be superimposed.
Example:
- Darvon (analgesic) vs. Novrad (cough suppressant).
- Changing orientation at the chiral center can change the potency and activity of a compound.

Pharmacophore: An ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interaction with a specific biological target and to trigger or block its biological response.
It's the area on the lead molecule responsible for its activity.
Alterations in the pharmacophore can improve or reduce potency.
Changes to the rest of the molecule can affect solubility, penetrability, and membrane diffusion.
Understanding the pharmacophore helps make informed changes to optimize the lead compound.

Uses computers to quantitatively analyze structure and activity relationships.
Generates and tests hundreds of slightly different compounds computationally.
Computer models reduce the number of potential leads to a manageable number for testing.

Atoms can be exchanged based on the number and arrangement of electrons in their outermost shells.
Monovalent, divalent, trivalent, and tetravalent groups can be interchanged.
Example:
- Replacing an oxygen in Rumenidine (antihypertensive drug with off-target effects) with $CH_2$ removes off-target effects without changing activity.
- Makes the drug specific for the target only.

These are methods to optimize a lead.
Optimization ensures that only the most promising and refined leads are taken to ADME and toxicity studies.