Med Chem 1 - unit 2 [in-progress]

What are the advantages of covalent bonds/drugs?

1. exceptionally high potencies and ligand efficiencies (LEs)

2. leads to high selectivity for targeted nucleophilic residues in appropriate position

What are the disadvantages of covalent bonds/drugs?

Toxicity risks associated with covalent modifications of proteins

What does the bond strength of covalent bonds range from?

50-150 kcal/mol

What is formed when most drugs interact with receptor binding sites?

What is their relationship strength compared to covalent bonds?

intermolecular bonds

- weaker than covalent

- means that they can be formed and broken w/in site of action

What type of bond is characterized by oppositely charged functional groups being attracted?

ionic (electrostatic) bond

What is the strength of ionic (electrostatic) bond?

What is the relationship between strength and distance?

strongest of intermolecular bonds

- 20-40 kJ mol ^-1

strength is inversely proportional to the distance b/w the two charged species

Where are ionic (electrostatic) bonds strongest?

hydrophobic environments (i.e., biological macromolecule binding sites)

ionic (electrostatic) bond are important w/ charged AAs at physiological pH. What are the charged AAs?

1. aspartate

2. glutamate

3. lysine

4. arginine

5. histidine

What type of bonds hold salts together?

salts

Salt of acidic drug molecule

Salt of basic drug molecule

Solvation

What atoms are attached to hydrogens in order to participate in hydrogen bonding?

What do these atoms contain?

highly electronegative atoms: O, N, Halogen

- causes hydrogen to become relatively (+) charged

LP of e-

- high density of (-) charge that's attracted to (+) species

What is the strength of hydrogen bonds?

What are some factors that influences the strength of bonding?

relatively strong bond

- 16-60 kJ mol^-1

- attraction b/w slight (+) H and the (-) LP

- angle at which H-bonding groups interact

- distance (1.5-2.2 A optimal)

- intensity of charge

How many LPs do H-bond acceptors require?

at least 1

Hydrogen bond acceptors (HBA)

HBA answers

What is the most electronegative element known?

What is it useful for in med chem?

fluorine

metabolic site blocking and comparative size to hydrogen

Why is their controversy around fluorine as a HBA?

1. studies showing fluorine hardly acts as HBA

2. CF3 is one of most lipophilic groups known

- on phenyl ring, has high degree of partial (-) charge and can HBA

What is the effect of hydrogen bonding in aromatic rings?

aromatic rings contain defuse cloud of circulating e- (overall negative charge)

acts as H-bond acceptor region

- BUT charge is weak compared to LP, so they are WEAK ACCEPTORS

When can aromatic rings have an effect on the molecular characteristics?

Which molecules are stronger and require most attention?

if all other HBO are excluded

O, N, F

What is the weak form of bonding existing between aromatic moieties when aligned in a parallel orientation?

pi pi stacking

- individual interactions weak, but multiple bonds can be really strong

When is pi pi stacking usually encountered?

when aromatic amino acid side chains (Tyr, Phe) that are positioned in such a way within the active site to interact with a drug molecule aromatic moiety.

Hydrogen bond donors (HBD)

What is a charged ionic group in one molecule that interacts with the oppositely charged dipole in another molecule?

ion-dipole interactions

Describe the strength of ion-dipole interactions

Stronger than a dipole-dipole interaction and can tolerate larger distances

What type of interactions occur when differing electronegativities of atoms comprising both the drug molecule and the binding site lead to the generation of a permanent dipole?

dipole-dipole interactions

When do dipole-dipole interacts interact and repel?

- interact when coming into close proximity, aligning drug so dipole moments in opposite directions (+ binding effect)

- if dipole moments aligned in same direction, leads to repulsion

Which interactions are very weak, where dipoles in one molecule leads to induction of dipole in a neighboring molecule, and occurs over very short distances?

Van der Waals Interactions (London Forces)

- excerpts influence when other forms of binding brings drug and binding sites into close proximity

What occurs if molecules come within too close proximity, leading to their orbitals beginning to overlap as do charged functional groups?

repulsion

ØEntropy is gained as the drug displaces the water in the binding site (positive entropy as more disordered H2O molecules). What does this lead to?

net gain in energy

- small effect but can be substantial over large surface area

Summary of molecular forces