Drug–DNA Interactions and Novel Drug Design D Gibson 276

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specific sequence on the double- Drug–DNA interactions and novel stranded genomic DNA include the design and preparation of single stranded drug design oligonucleotides or PNAs capable of either forming a triple helix with the D Gibson* specific ds-DNA sequence that has been targeted (antigene strategy) or can selectively target the single-stranded Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The messenger RNA (antisense strategy).1,2 Hebrew University of Jerusalem, Jerusalem, Israel In addition to the exploitation of the known double helical structure of B- *Affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem, DNA, the discovery of novel types of Israel. DNA motifs, such as the quadruplex DNA that is formed at the end of the The Pharmacogenomics Journal (2002) 2, it is more efficient to treat a disease by telomeres, provides additional specific 3 275–276. doi:10.1038/sj.tpj.6500133 designing drugs that act at the DNA targets for drug binding. or messenger RNA level rather than at The molecular basis for designing Small molecules that bind genomic the protein level. DNA binding drugs with improved DNA have proven that they can be The design of novel drugs or of specificity and affinity stems from the effective anticancer, antibiotic and improved higher generation therapeu- ability to identify the structural ele- antiviral therapeutic agents that affect tics is a complex task that goes beyond ments of the drug that are responsible the well-being of millions of people improving the specificity of the drug for the specificity of the binding and worldwide. to its biological target. Since in many for the stabilization of the drug–DNA DNA is the pharmacological target cases, only a minute fraction of the complex. Once these parameters are of many of the drugs that are currently administered drug reaches the critical identified, novel analogs with im- in clinical use or in advanced clinical pharmacological target, strategies for proved selectivity and affinity can be trials. Targeting DNA to regulate cell increasing the drug’s accumulation in synthesized and screened. The impor- functions by modulating gene expres- the vicinity of the cellular DNA must tance of understanding the nature of sion or by interfering with replication be devised. Thus, drug delivery strate- these interactions was recognized early seems logical, intuitively appealing gies should strive to prolong circula- on, and already in the 1940s simple and conceptually straightforward. tion time, enhance tissue-specific acridines and proflavin molecules that With the new wealth of information accumulation, increase the effective- were used as antibacterial agents were provided by the Human Genome ness of cellular and nuclear uptake in also utilized as probes for the study of 4 Project, it was expected that this addition to high specificity and affi- mutagenesis. In the mid-1950s the information would lead to a quantum nity towards the DNA. The complexity correlation between DNA binding and 5 leap in the development of DNA- of the biological system makes it very biological activities was established. binding pharmaceuticals since this difficult to simultaneously incorporate The study of the interactions of small information should facilitate the elu- all of these factors into a single algo- molecules with DNA has advanced cidation of the roles that different rithm for drug design. Focusing on hand in hand with the advances in genes play in important pathological specificity is relatively straightforward molecular biology, biophysical meth- processes. Pharmacology is thought to since the structure of the DNA is well ods, chemical synthesis, analytical in- be a major potential beneficiary from known. strumentation and computational the completion of the first draft of the Many strategies have been devel- capabilities. It is noteworthy that out Human Genome Project since in the oped to exploit the known structure of the 100 most cited papers in the post-genomic era, it seems quite plau- Journal of Molecular Biology, eight of the DNA for specific drug binding. sible that in the near future it may be papers describe drug–DNA interactions. One approach is to use small mole- possible to combine genomics and But the structural details of the cules that are able to recognize sur- pharmacology in order to administer drug–DNA complex alone do not pro- specific individual treatments based faces that are unique to the DNA and vide all the necessary information for on the individual’s genotype. Although can bind to specific regions in the drug design. Well over half a century in the ‘post genomic’ era the fields DNA such as the major groove, the ago Scatchard noted that the following of functional genomics and proteo- minor groove or between the DNA questions ‘How many? How tightly? mics have been receiving increasing bases at specific sequences. Other Where? Why? What of it?’ must be attention, many researchers feel that approaches toward recognition of a answered in order to understand the Drug–DNA interactions and novel drug design D Gibson 276

fundamentals of ligand binding to double-stranded DNA by insertion of etc. The discovery of this new inter- DNA.6 There is not one single experi- the planar moiety between adjacent calation specificity provides the drug mental technique that can provide the base pairs of the double helix.12 The designers with another building block answers to all these questions and hydrophobic (stacking) interactions to use in the construction of novel thus, many approaches have been stabilize the complex. DNA binders. developed to elucidate drug–DNA in- In a recent paper, Lisgarten et al It is pleasing to realize that even teractions.7 Effective drug design re- show by competition dialysis that the after so many years of investigations of quires a sufficiently clear and detailed antimalarial drug cryptolepine binds drug–DNA interactions there are still picture of the drug–DNA interactions, preferentially to the non-symmetric novel types of interactions to be dis- a picture that can only be unraveled by d(CC)/d(GG) site and they also de- covered. The ultimate test of the value combining the information from the scribe the X-ray crystal structure of the of such a study is whether it will serve different approaches to the study of complex between cryptolepine and as a basis for the design of improved drug–DNA interactions. It is impera- double-stranded self-complementary DNA binding drugs. tive to obtain a detailed view of the hexadeoxynucleotide d(CCTAGG).13 drug–DNA complex; to know the ki- The most noteworthy result of this netics and mechanism of the drug study is the detailed description of the binding and to measure the energetics architecture of the drug–DNA complex DUALITY OF INTEREST None declared. involved in these interactions. A de- of a hitherto unknown type of base tailed three-dimensional view of the specificity where the drug is interca- drug–DNA interactions, at atomic re- lated in a non-symmetric d(GG/CC) Correspondence should be sent to solution, can only be obtained by the site. To date, in all of the DNA– Dr D Gibson, Department of Medicinal construction of simplified models con- intercalator complexes that have been Chemistry and Natural Products, School of sisting of stable drug–oligonuceotide characterized by X-ray crystallography, Pharmacy, PO Box 12065, The Hebrew adducts that can be subjected to high- the intercalators, both parallel and University of Jerusalem, Jerusalem 91120, Israel Tel: 972 2 6758702 resolution structural analysis by single perpendicular, were bound in alternat- Fax: 972 2 6757076 crystal X-ray crystallography and/or by ing pyrimidine–purine sites, mostly to E-mail: [email protected] NMR spectroscopy.8,9 These techniques d(CG) and to a lesser extent to d(GC) can provide the three-dimensional de- and d(TG). The authors identified the tails of the drug–DNA interactions, but main structural feature (the positively they cannot shed light either on the charged N18) responsible for the sta- 1 Casey BP et al. Prog Neucleic Acid Res Mol Biol mechanism of binding or on the bility of the complex, and noted that 2001; 67: 163–192. energetics of the interactions. in an isomer with a lower affinity to 2 Gambari R. Curr Pharm Des 2001; 7: 1839– 14 1862. The Nucleic Acid Data Bank (NDB) DNA (neocryptolepine) the charged 3 Raymond E et al. Invest New Drug 2000; 18: contains B100 structures of drug– nitrogen is located in the sixth posi- 123–137. DNA complexes depicting the various tion. The binding of cryptolepine to 4 Brenner S et al. J Mol Biol 1961; 3: 121. modes by which small molecules bind the d(CC)/d(GG) site produced a DNA 5 Peacocke AR et al. Trans Faraday Soc 1956; 10 52: 261. to double-stranded DNA. Small mo- structure that is reminiscent of those 6 Scatchard G. Ann N Y Acad Sci 1949; 51: lecules bind to DNA either covalently formed by other drug–intercalator 660. (for example cisplatin and nitrogen complexes and hence the influence 7 Chairns JB, Waring MJ (eds). Methods in mustards),11 or non-covalently by the of the binding specificity on down- Enzymology Vol340. 2001, San Diego Aca- demic Press. formation of hydrogen bonds, electro- stream binding and recognition events 8GaoXLet al. Q Rev Biophys 1989; 22: 93– static and/or hydrophobic interac- may not be unique. 138. tions. The non-covalent binders are There have been many attempts to 9 Haq I et al. J Mol Recog 2000; 13: 188–197. divided into two types: minor groove incorporate different types of DNA 10 Berman HM et al. Prog Biophys Mol Biol 1996; 66: 255. binders (distamycin, netropsin and binding moieties into one molecule 11 Cohen SM et al. Prog Nucleic Acid Res Mol Hoechst 33258) and intercalators in the hope of increasing specificity Biol 2001; 67: 93–130. (doxorubicin, acridine orange, etc.). and affinity. Alkylators have been com- 12 Lerman LS J Mol Biol 1961; 3: 18. Intercalators are molecules that have bined with intercalators, intercalators 13 Lisgarten JN et al. Nat Struct Biol 2002; 9: 57–60. a planar moiety usually comprised of have been linked to each other to 14 Bially C et al. Anticancer Drug Des 2000; 15: several fused rings, that interacts with form bis-, tris- and poly-intercalators, 191–201.

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