Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

José Portugal

doi:10.1186/1471-2210-9-11

Abstract

BackgroundSmall molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.ResultsFifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute's drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.ConclusionFor drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute's 60-cell line data set tend to have common structural features.

Highlights

Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy
Drugs that bind reversibly to DNA can be characterized by common molecular descriptors, as well as by their DNAbinding constant Table 1 shows six common molecular descriptors, XlogP, molecular weight (Mw), number of potential hydrogen bond acceptors (HbA), potential hydrogen bond donors (HbD), polar surface area (PSA) and complexity
The complexity rating of a compound is the rough estimate of how complicated a structure is, seen from both the point of view of the elements contained and the displayed structural features including symmetry

Summary

Introduction

Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. Most of the drugs than bind noncovalently to DNA, such as actinomycin D and several anthracyclines [1,3], interact selectively with the nucleic acid along the minor groove or by intercalation. The strength of reversible binding to DNA can be quantified for any drug by means of the equilibrium binding constant (Keq). DNA-binding data, which may be used to correlate noncovalent drug-DNA interactions with cytotoxicity data, should be regarded as 'approximate values' com-

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