Investigation of DNA‐Binding Properties of Organic Molecules Using Quantitative Structure‐Activity Relationship (QSAR) Models

ABSTRACTDue to the great potential of DNA as a receptor, many classes of synthetic and naturally occurring molecules exert their anticancer activities through DNA‐binding. In the field of antitumor DNA‐binding agents, a number of acridine and anthracycline derivatives are in the market as chemotherapeutic agents. However, the clinical application of such classes of compounds has encountered problems such as multi‐drug resistance and secondary and/or collateral effects. Thus, there has been increasing interest in discovering and developing small molecules that are capable of DNA‐binding, which will be expected to be used either in place of or in conjunction with, the existing compounds. The interest in the application of the QSAR paradigm has steadily increased in recent decades and we hope it may be useful in the design and development of DNA‐binding molecules as new anticancer agents. In the present review, an attempt has been made to understand the DNA‐binding properties of different compound series and discussed using 27 QSAR models, which reveal a number of interesting points. The most important determinants for the activity in these models are Hammett electronic (σ and σ+), hydrophobic, molar refractivity, and Sterimol width parameters. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:88–110, 2008