The physicochemical approach to drug design and discovery (QSAR)

Abstract

The study of physicochemical parameters to correlate mathematically chemical structure with biological activity induced by sets of congeneric drugs is now generally referred to as QSAR (quantitative structure‐activity relationships). The ways in which the QSAR paradigm are developing are becoming more varied and complex. Many kinds of parameters are under study in many different groups; various types of mathematical models have been proposed and are being evaluated. Drug researchers are turning more to enzyme modulation to control various biological processes. It is the study of enzyme‐ligand reactions of enzymes whose x‐ray crystallographic structure is known that affords us the means for developing a deeper understanding of QSAR and, at the same time, enhancing our ability to make drugs more selective for various forms of a given enzyme. The union of x‐ray crystallography, moleculargraphics, and QSAR is one of the most exciting new areas of drug development. This report is an introduction to how QSAR is being used to gain insight into the interaction of drugs with macromolecules and macromolecular systems.

A New Strategy of High-Speed Screening and Quantitative Structure-Activity Relationship Analysis to Evaluate Human ATP-Binding Cassette Transporter ABCG2-Drug Interactions

“…To facilitate our understanding of drug absorption and distribution, Hansch developed a QSAR analysis method (Hansch, 1981). Initially, he studied the role of octanol/water partition coefficients (logP) in drug transport processes that were thought to contribute to drug absorption and distribution in our body.…”

Quantitative structure-activity relationship studies of cyclooxygenase inhibitors: a comprehensive analysis

“…It is a measure of volume and polarizability of the whole molecules. Aromatic substituent constants like the Hansch Hydrophobic constant (p), Molar Refractivity (MR), Hammet's electronic constant (s), Field effect ( f ), and Resonance (R) were taken from the literature [Hansch andLeo, 1995, 1979;. The steric parameters were derived from Verloop et al's [1976] compilation.…”

“…A recent QSAR review reported by Garg and colleagues [Garg et al, 2003] provides a plethora of information regarding most of the most important classes of COX inhibitors. Since the seminal work of Hansch almost 40 years ago, QSAR research has been considered as a major tool in the drug design process as an effective way of optimizing or correlating the biological activity within congeneric series either with certain structural features or with atomic, group, or molecular descriptors, such as lipophilicity, polarizability, electronic, and steric properties [Hansch, 1981]. Exploration of physicochemical and structural requirements of different selective COX-2 inhibitors through QSAR studies has been a long-time research focus in our laboratory [Prasanna et al, 2004a[Prasanna et al, -d, 2005aManivannan et al, 2004].…”

CoMFA and CoMSIA studies on thiazolidin-4-one as anti-HIV-1 agents

“…Drug-resistant viruses of NNRTIs point out the need for continuing the search for novel anti-HIV-1 drugs [5]. In drug design and discovery research quantitative structure-activity relationship (QSAR) studies provide rational inputs for molecular modifications [6,7]. In this endeavor, various computational strategies, such as quantum mechanical applications, 2D QSAR/3D QSAR and structure-based drug design approach have been applied to several classes of NNRTIS [8][9][10][11][12][13].…”