JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B.Pharmacy II Year MEDICINAL CHEMISTRY-I Previous Question Paper (November/December - 2020 - R17)

Physicochemical properties determine how a drug molecule interacts with biological systems, influencing its pharmacokinetic and pharmacodynamic profiles. Key properties include:

• Lipophilicity (Partition Coefficient, log P): This is the most critical factor for membrane permeability. A balanced log P is required for a drug to cross lipid bilayers while remaining soluble in aqueous physiological fluids.
• Ionization (pKa): The degree of ionization at physiological pH (7.4) dictates the ratio of ionized to unionized forms. The unionized form typically crosses cell membranes, while the ionized form often interacts with target receptors via ionic bonding.
• Solubility: Aqueous solubility is essential for drug absorption and systemic distribution. Poor solubility often limits bioavailability.
• Hydrogen Bonding: The ability to form hydrogen bonds influences target binding affinity and specificity, as well as the drug's interaction with water molecules.
• Molecular Weight and Size: These influence the rate of diffusion and the ability of the drug to fit into the binding pocket of a macromolecular target.
• Steric Factors: The spatial arrangement of atoms determines the drug's ability to achieve a precise fit with a receptor, influencing potency and selectivity.

Bioisosterism is the substitution of an atom or a group of atoms in a drug molecule with another atom or group having similar physical or chemical properties, which produces broadly similar biological effects. This strategy is used to reduce toxicity, modify activity, or improve the pharmacokinetic profile of a lead compound.

Bioisosteres are classified into two main types:

• Classical Bioisosteres: These involve atoms or groups with similar electronic configurations and valence electrons. Examples include monovalent atoms (F, Cl, OH, NH2, CH3) or divalent groups (O, S, NH, CH2).
• Non-classical Bioisosteres: These do not follow the strict electronic or steric rules of classical bioisosteres but produce similar biological results. They may differ in the number of atoms or electronic structure but maintain similar spatial arrangements or functional capabilities.

A classic example is the substitution of a hydrogen atom with a fluorine atom. Because fluorine is similar in size to hydrogen but significantly more electronegative, it can block metabolic oxidation at that site, thereby increasing the drug's half-life without significantly altering its receptor binding affinity.