Notes on Drug Action: Covalent vs Non-covalent Interactions

Drug Action Fundamentals

• Drug: a chemical substance of known structure (not an essential dietary ingredient) that, when administered to a living organism, produces a biological effect; used to treat, cure, prevent, or diagnose disease or promote well-being.
• Drug Targets: molecules in the body intrinsically linked to disease processes (proteins such as enzymes, receptors, channels; nucleic acids like DNA, RNA); addressed by a drug to achieve therapeutic effect.
• Drug–Target Interaction principle:
  • A drug (I) binds to its target (E) to form the drug–target complex (EI).
  • The EI complex changes the conformation of the target.
  • The EI complex has lower energy than the sum of separate drug and target: \Delta G{\text{bind}} = G{EI} - (GE + GI) < 0.
  • Binding energy relates to overall affinity of the drug for the target.

Covalent vs Non-covalent Bonds in Drug Action

• Most drugs bind via non-covalent interactions; a balance of multiple interactions determines overall affinity and reversibility.
• Covalent bonds are less common in drugs; form lasting, often irreversible bonds; can lead to long duration of action and potential off-target effects.
• Covalent bond energy range: $E_{\text{covalent}} \approx 200\text{--}500\ \text{kJ/mol}.$
• Non-covalent bonds are reversible; binding strength decreases with distance between interacting groups.

Covalent Bonds in Drugs

• General features:

  • Involve sharing of electron pairs; octet rule governs stability.
  • Bond types form via different hybridizations (sp3, sp2, sp).
  • Only a small number of drugs form covalent bonds with targets.
  • Consequences: high energy, often irreversible; potential lack of selectivity and long duration; may require special handling due to reactivity.

• Alkylation

  • Mechanism: drug adds an alkyl group (CnH2n+1−) to a target (e.g., guanine in DNA).
  • Medical use: cancer therapy (alkylating antineoplastic agents).
  • Examples: nitrogen mustards; covalent interaction with target.
  • Notable example: Ibrutinib covalently binds Bruton's tyrosine kinase (BTK) at C481.

• Acylation

  • Mechanism: drug adds an acyl group (RCO−) to a target; targets include ester, lactone, amide, carbamate functional groups.
  • Drug–target nucleophile: N, S, or O atoms on the target.
  • Examples:
  • Aspirin acetylates a serine in COX enzyme.
  • β-lactam antibiotics acylate DD-transpeptidase (PBP) to inhibit cell wall synthesis.
  • Acetylcholinesterase inhibitors involve acylation processes.

• Phosphorylation

  • Mechanism: drug adds a phosphate group to a target.
  • Example: organophosphates irreversibly phosphorylate acetylcholinesterase (highly toxic; used as insecticides).

• Rearrangement (metabolic) covalent interactions

  • Occurs during metabolism; active metabolite can form covalent bonds with targets or proteins (e.g., formation of disulfide bonds).
  • Example: clopidogrel and its active metabolite can form covalent interactions via thiol/disulfide chemistry with proteins.

• Summary of covalent bonds

  • Covalent bond energy: $E<em>{\text{covalent}} \gg E</em>{\text{non-covalent}}.$
  • Key considerations: irreversible bonds, duration of action, potential adverse effects, handling/reactivity concerns.

Non-covalent Bonds in Drug Action

• Most drug–target binding is non-covalent and reversible.
• Overall binding strength is the sum of individual non-covalent interactions; determines affinity.
• The strength of non-covalent interactions is inversely proportional to the distance between interacting groups.
• Key non-covalent interactions: ionic, dipole, hydrogen bonds, van der Waals, hydrophobic, aromatic interactions, and others (e.g., π–π, cation–π).
• Energies (per interaction):
  • Ionic (electrostatic): $E_{\text{ionic}} \approx 20\text{--}40\ \text{kJ/mol}.$
  • Hydrogen bonds: $E_{\text{H-bond}} \approx 16\text{--}60\ \text{kJ/mol}.$
  • Dipole–dipole: $E_{\text{dipole-dipole}} \approx 2\text{--}8\ \text{kJ/mol}.$
  • Dipole–ion interactions are stronger than simple dipole–dipole.
  • van der Waals: $E_{\text{vdW}} \approx 2\text{--}4\ \text{kJ/mol}$ per interaction; cumulative effects can be significant.
• Hydrogen bond details:
  • Donor: hydrogen attached to highly electronegative atom (F, O, N).
  • Acceptor: electronegative atom (F, O, N).
  • Typical strength: $E_{\text{H-bond}} \approx 16\text{--}60\ \text{kJ/mol}.$
• Dipole and ion-related interactions:
  • Ion–dipole: interactions between a charged group and a dipole; higher energy than dipole–dipole.
  • Dipole–dipole: electrostatic attraction between polar groups.
• Aromatic interactions (π–π, cation–π): important binding forces in some drug–target interfaces.

Ionization, pH, and Bonding Considerations

• At physiological pH (~7.2), ionization state of groups affects ionic bonding:
  • Acids (HA) vs. conjugate base (A−) balance governed by pKa and pH via Henderson–Hasselbalch relation:
  • Correct form: $\text{pH} = \text{p}K<em>a + \log</em>{10}\left(\frac{[A^-]}{[HA]}\right).$
• Examples at pH 7.2:
  • Acids with low pKa (e.g., CH3COOH) predominantly exist as CH3COO− at physiological pH.
  • Bases with high pKa (e.g., alkylamines) predominantly exist as BH+ at physiological pH.
• Ionic bonds form between positively charged residues (e.g., Lys, Arg) and negatively charged residues (e.g., Asp, Glu) on targets.

Chelation and Complexation

• Chelation: binding of a metal ion by a ligand at two or more points to form a coordination complex.
• Relevance to drug action: some drug–target interactions involve coordinate bonds with metal ions (e.g., Ca2+), potentially affecting activity.
• Examples and considerations:
  • Tetracycline can chelate Ca2+ in the GI tract, reducing activity when taken with calcium.
  • Ciprofloxacin can chelate metal ions; timing with meals containing calcium or other metals matters.

Aromatic and Additional Interactions

• Aromatic interactions: π–π stacking between drug and aromatic residues (Phe, Tyr, Trp) in the target.
• Cation–π interactions: positive drug groups interacting with aromatic rings in the target.
• Chelation and complexation can also influence binding and activity via metal coordination.

Summary Takeaways

• A drug must bind its target to exert a therapeutic effect.
• A small fraction of drugs act via covalent bonds; most rely on non-covalent interactions.
• Non-covalent interactions collectively determine binding strength (affinity) and reversibility.
• Bond strength order (typical): \text{Covalent} \gg E{\text{ionic}} \approx E{\text{H-bond}} \; >\; E{\text{dipole-dipole}} \; >\; E{\text{vdW}} \; (\text{hydrophobic interactions})
• The strength of non-covalent bonds is inversely related to distance between drug and target functional groups.
• Important practical notes:
  • Some drugs act via alkylation, acylation, phosphorylation, or rearrangement covalent mechanisms.
  • Many pharmacologic interactions rely on reversible non-covalent bonds (ionic, dipole, H-bonds, vdW, hydrophobic, aromatic).
  • pH and ionization states influence the formation of ionic bonds at physiological conditions.

Quick reference points

• Corpera non agunt nisi fixate (A drug cannot act unless bound).
• Covalent bond energy is high and often irreversible; careful therapeutic considerations needed.
• Non-covalent bonds provide specificity and reversibility; binding strength is additive across interactions.