The application of bioisosteres in drug design for novel drug discovery: focusing on acid protease inhibitors.

INTRODUCTION: A bioisostere is a powerful concept for medicinal chemistry. It allows the improvement of the stability; oral absorption; membrane permeability; and absorption, distribution, metabolism and excretion (ADME) of drug candidate, while retaining their biological properties. The term 'bioisostere' is derived from 'isostere', whose physical and chemical properties, such as steric size, hydrophobicity, and electronegativity, are similar to those of a functional or atomic group, and is considered to possess biological properties. Here, the authors highlight the recent applications of bioisosteres in drug design, mainly based on our drug discovery studies. AREAS COVERED: This review discusses the application of bioisosteres for novel drug discovery with focus on the authors' drug discovery studies such as renin, HIV-protease, and β-secretase inhibitors. The authors highlight that some bioisosteres can form the scaffolding for drug candidates, namely substrate transition state, amide/ester, and carboxylic acid bioisosteres. Moreover, the authors propose the new terms 'electron-donor bioisostere' and 'conformational bioisostere' for drug discovery. EXPERT OPINION: The authors discuss the importance of bioisostere's design concept based on specific interaction with the corresponding biomolecule. In addition, some strategies for drug discovery based on the bioisostere concept are introduced. Many bioisosteres, which are recognized by corresponding target biomolecules as exhibiting similar biological properties, have been reported to date; most of the recently developed bioisosteres were designed by cheminformatics approaches. Some molecular design softwares and databases are introduced.