Development and use of hydrophobic surface area (HSA) descriptors for computer-assisted quantitative structure-activity and structure-property relationship studies

Abstract

A new series of 25 whole-molecule molecular structure descriptors are proposed. The new descriptors are termed Hydrophobic Surface Area, or HSA descriptors, and are designed to capture information regarding the structural features responsible for hydrophobic and hydrophilic intermolecular interactions. The utility of the HSAs in capturing this type of information is demonstrated using two properties that have a known hydrophobic component. The first study involves the modeling of the inhibition of Gram-positive bacteria cell growth of a Series of biarylamides. The second application involves the study of the blood-brain barrier penetration of a diverse series of drug molecules. In both cases, the HSAs are shown to effectively capture information related to the hydrophobic components of these two properties. Additional evaluation of the new class of descriptors shows them to be unique in their ability to measure hydrophobic features among a diverse set of conventional structural descriptors. The HSAs are evaluated regarding their sensitivity to conformational changes and are found to be similar in that regard to other widely used molecular descriptors.