Prediction of noncovalent Drug/DNA interaction using computational docking models: Studies with over 1350 launched drugs

Abstract

Noncovalent chemical/DNA interactions, for example, intercalation and groove-binding, may be more important to genomic integrity than previously appreciated, and there may very well be genotoxic consequences of that binding. It is of importance, then, to develop methods allowing a determination or prediction of such interactions. This would have particular utility in the pharmaceutical industry where genotoxicity is, for the most part, disallowed in new drug entities. We have previously used DNA docking simulations to assess if molecules had structure and charge characteristics which could accommodate noncovalent binding via, for example, electrostatic/hydrogen bonding. We here extend those earlier studies by examining a series of over 1,350 "launched" drugs for ability to noncovalently bind 10 different DNA sequences using two computational programs: Autodock and Surflex. These drugs were also evaluated for binding to the crystallographic ATP-binding site of human topoisomerase II. The results obtained clearly demonstrate multiple series of noncovalent DNA binding structure activity relationships which would not have been predicted based on cursory structural examination. Many drugs within these series are genotoxic although not via any commonly recognized structural covalent alerts. The present studies confirm previously implicated features such as N-dialkyl groups and specific N-aryl ketones as potential genotoxic chemical moieties acting through noncovalent mechanisms. These initial studies provide considerable evidence that DNA intercalation may be an important, largely overlooked, source of drug-induced genotoxicity and further suggest involvement of topoisomerase in that genotoxicity.

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

“…With the current increase in availability of both gene sequences and the knowledge of their functions in life‐forms ranging from bacteria to humans, there is clearly an unmet need for new, sequence‐specific, small‐molecule DNA probes . Significant variations in the cell‐uptake potential of molecular structures and pharmacokinetic differences will also require discovery and development of a diversity of different molecular systems for DNA recognition that do not currently exist …”

“…[7,9,15] Significant variations in the cell-uptake potentialo fm olecular structuresa nd pharmacokinetic differences will also require discoverya nd development of ad iversity of different molecular systems for DNA recognition that do not currently exist. [16][17][18][19]…”

A source of artifact in the lacZ reversion assay in Escherichia coli

“…mutagenesis or a precursor that may (or may not) be processed into frameshifts. We used compounds whose structures do not suggest intercalation but that are thought to intercalate on the basis of computer modeling [6,7], displacement of ethidium from DNA [8], and interaction with bleomycin in genotoxicity assays in Chinese hamster cells [9] and yeast [10]. We observed strong mutagenicity for reactive acridine derivatives, as expected, and weakly positive responses for the other compounds, some of which had earlier yielded negative results for mutagenicity in our laboratory and elsewhere.…”

In Vitro and Computational Assessment of Genotoxic Potential of Active Constituents Present in Three Medicinally Important Plant Extracts

“…Requirement of such method leads to the generation of molecular docking and simulation which encompasses the determination of the nature of interactions between molecules such as hydrogen bonding , electrostatic interaction or anything else (Snyder et al, 2013).…”