Dual Nature of Molecules: Amphiphilicity as a Missing Descriptor in Drug Design

Abstract Current drug-design approaches rely heavily on global molecular descriptors, including lipophilicity, hydrogen-bonding capacity, molecular weight, and polar surface area. Although valuable, these descriptors provide limited insights into drug behavior at biomembrane interfaces, where steep polarity gradients occur. We propose molecular amphiphilicity as a complementary descriptor relevant to pharmacokinetics and pharmacodynamics. Arising from the spatial segregation of hydrophilic and hydrophobic regions, amphiphilicity influences drug–membrane association, orientation, and permeation. We introduce a molecular-dynamics-based methodology to quantify the magnitude and orientation of the amphiphilic moment in membrane environments. Applied to selected amphiphilic molecules, this approach provides insights into membrane interactions and motivates broader evaluation of the amphiphilic moment as a complementary molecular descriptor in drug design.