ABSTRACT

The pharmacophore concept is well known and routinely used in drug design processes. This chapter briefly discusses and characterizes some well-known pharmacophores of different receptors. The concept of multisite pharmacophores is also proposed, and methods to predict selectivity properties are discussed. The principle of a simple triangular shape of a pharmacophore is explained to gain a better understanding of selectivity. It helps the ligand to remain in a proper orientation to maximize its electrostatic interaction with the receptor. Constructing a pharmacophore of muscarinic receptor ligands is based on the selection and alignment of the prominent charges in the ligands. A pharmacophore built in this way is in good agreement with the Kier formula. The recognition signature concept is also introduced and discussed herein. It is a set of features of electronic structure and molecular geometry that should be conserved to keep the molecular scaffold selective to the specific receptor. Drug selectivity and affinity are not correlated, and examples show that an increase in affinity does not always relate to improving selectivity. Conformational changes in protein and ligand are often a key factor for recognition where timescale and energy of conformational transition may prevent or promote better recognition of drugs.