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Recent Advances in Developing Small Molecules Targeting Nucleic Acid

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Recent Advances in Developing Small Molecules Targeting Nucleic Acid International Journal of Molecular Sciences Review Recent Advances in Developing Small Molecules Targeting Nucleic Acid Maolin Wang 1,2,3, Yuanyuan Yu 1,2,3, Chao Liang 1,2,3, Aiping Lu 1,2,3,* and Ge Zhang 1,2,3,* 1 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China; [email protected] (M.W.); [email protected] (Y.Y.); [email protected] (C.L.) 2 Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen 518000, China 3 Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China * Correspondence: [email protected] (A.L.); [email protected] (G.Z.); Tel.: +852-3411-2456 (A.L.); +852-3411-2958 (G.Z.) Academic Editor: Mateus Webba da Silva Received: 2 March 2016; Accepted: 9 May 2016; Published: 30 May 2016 Abstract: Nucleic acids participate in a large number of biological processes. However, current approaches for small molecules targeting protein are incompatible with nucleic acids. On the other hand, the lack of crystallization of nucleic acid is the limiting factor for nucleic acid drug design. Because of the improvements in crystallization in recent years, a great many structures of nucleic acids have been reported, providing basic information for nucleic acid drug discovery. This review focuses on the discovery and development of small molecules targeting nucleic acids. Keywords: nucleic acids; nucleic acids targeting; small molecules; DNA drug discovery; RNA drug discovery 1. Introduction Nucleic acids play significant roles in variety kinds of biological processes [1–5]. According to the differences on sugar scaffold, nucleic acids can be classified into two categories. DNAs and RNAs participate in gene storage, replication, transcription and other important biological activities. Thus, targeting nucleic acids can regulate a large range of biological processes, especially genetic diseases. Nucleic acids play significant roles in anticancer [6] and antiviral [7] processes. Therefore, the small molecules targeting nucleic acids are desirable and have become a topic issue in recent years. However, small molecules targeting nucleic acids are more difficult to discover than targeting protein, which result from various reasons. Nucleic acid lacks spatial structure information from X-ray crystallization, nuclear magnetic resonance (NMR) or other imaging methods. Current approaches for small molecules targeting protein are incompatible with nucleic acids. Most of the docking methods, for example, do not regard RNA and DNA receptors as flexible bodies [8–10], which constrains the conformational changes of nucleic acids. Fortunately, the areas of structural biology and computational chemistry have improved dramatically. A large number of structures of nucleic acids have been reported. Several computational methods and force fields have been developed and modified [11,12]. These improvements provide a new horizon to discovery and design novel small molecules targeting nucleic acids. Depending on the differences on sugar scaffold of nucleic acids, small molecules targeting nucleic acids can be separated into two main categories: small molecules targeting DNA and small molecules targeting RNA (in which DNA and RNA can form different conformations). This review focuses on the recent discovery and development of small molecules targeting DNA and RNA. Int. J. Mol. Sci. 2016, 17, 779; doi:10.3390/ijms17060779 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 779 2 of 24 2. SmallInt. J. MoleculesMol. Sci. 2016, 17 Targeting, 779 DNA 2 of 23 Int. J. Mol. Sci. 2016, 17, 779 2 of 23 2.1. Small2. Small Molecules Molecules Targeting Targeting DNA DNA Duplex 2. Small Molecules Targeting DNA 2.1.1.2.1. Small Small Molecules Molecules FormingTargeting DNA Covalent Duplex Bonds with DNA Duplex 2.1. Small Molecules Targeting DNA Duplex Psoralen2.1.1. Small or Molecules psoralene Forming has been Covalent used asBonds mutagen with DNA to treat Duplex skin diseases including psoriasis and vitiligo. Psoralen interacts with standard DNA duplex, through the 5,6 double bond in pyrimidine ring, 2.1.1.Psoralen Small Molecules or psoralene Forming has beenCovalent used Bonds as mutagen with DNA to treat Duplex skin diseases including psoriasis and which can stop replication and transcription. 41-(Hydroxymethyl)-4,51,8-trimethylpsoralen, short for vitiligo.Psoralen Psoralen or psoralene interacts withhas been standard used DNAas mutagen duplex, to through treat skin the diseases 5,6 double including bond inpsoriasis pyrimidine and HMT,ring,vitiligo. has reasonablewhich Psoralen can waterinteractsstop replication solubility with standard andand hightranscription. DNA DNA duplex, binding 4 ′through-(Hydroxymethyl)-4,5 affinity, the 5,6 as double shown′,8-trimethylpsoralen, bond in Figure in pyrimidine1A. Figure 2B showsshortring, the which crystalfor HMT, can structure hasstop reasonable replication of a short water and DNA transcription.solubility complex and 4 with ′high-(Hydroxymethyl)-4,5 HMTDNA reportedbinding af′ by,8-trimethylpsoralen,finity, Spielmann as shownet in al. [13]. The HMTFigureshort structurefor 1A. HMT, Figure crosseshas 2B reasonableshows both the the crystalwater minor structuresolubility and majorofand a short high grooves DNA DNA complex throughbinding with af thefinity, HMT 5,6 doubleas reported shown bonds byin of pyrimidineSpielmannFigure ring1A. etFigure and al. [13]. two 2B The thymines.shows HMT the structure crystal There structure arecrosses apparent both of a theshort stacking minor DNA and interactions complex major grooveswith from HMT through the reported ring the system 5,6by of HMTdoubleSpielmann and the bonds bases et al. of nearby. [13].pyrimidi The The HMTne ring high structure and binding two crosses thymines. affinity both ofThere the HMT minor are and apparent and duplex major stacking resultsgrooves interactions fromthrough aromatic the from 5,6 rings stackingthedouble andring bonds hydrophobicsystem of of pyrimidi HMT interactions. andne thering bases and The twonearby. crystal thymines. The study high There ofbinding the are complexapparent affinity of stacking HMT DNA and andinteractions duplex HMT results showed from the from aromatic rings stacking and hydrophobic interactions. The crystal study of the complex of DNA Hollidaythe ring junction system was of HMT formed and in the the bases adduct nearby. of DNA-HMT.The high binding The affinity interaction of HMT between and duplex DNA results and HMT andfrom HMT aromatic showed rings the stacking Holliday and junctionhydrophobic was formedinteractions. in the The adduct crystal of study DNA-HMT. of the complex The interaction of DNA is related with sequence, which may play a role in repairing the psoralen damage in chemotherapy betweenand HMT DNA showed and theHMT Holliday is related junction with sequence,was formed which in the may adduct play aof role DNA-HMT. in repairing The the interaction psoralen treatment.damagebetween The inDNA conformationchemotherapy and HMT is oftreatment. related DNA iswith The extremely sequence,conformati twisted whichon of mayDNA at the play is bases extremely a role of thyminein twistedrepairing connectedat thethe psoralenbases with of the hexatomicthyminedamage pyrone inconnected chemotherapy of the with molecule. the treatment. hexatomic The pyrone conformati of theon molecule. of DNA is extremely twisted at the bases of thymine connected with the hexatomic pyrone of the molecule. Figure 1. (A) Chemical structure of HMT; and (B) NMR structure of a short DNA complex with HMT Figure 1. (A) Chemical structure of HMT; and (B) NMR structure of a short DNA complex with HMT (RCSBFigure Protein1. (A) Chemical Data Bank structure (PDB) code: of HMT; 204D). and The (B) oranNMRge structure structure of represents a short DNA the smallcomplex molecule. with HMT The (RCSB Protein Data Bank (PDB) code: 204D). The orange structure represents the small molecule. purple(RCSB Proteinstructure Data represents Bank (PDB) the code:backbone 204D). of The nucleic oran geacid; structure the blue represents and red theatoms small in molecule.the molecule The The purple structure represents the backbone of nucleic acid; the blue and red atoms in the molecule representpurple structure nitrogen represents and oxygen the atoms, backbone respectively. of nucleic acid; the blue and red atoms in the molecule representrepresent nitrogen nitrogen and and oxygen oxygen atoms, atoms, respectively. respectively. Figure 2. (A) Chemical structure of Aflatoxin B1 adduct; and (B) NMR structure of a DNA duplex complex with Aflatoxin B1 adduct (PDB code: 2KH3). The orange structure represents the small FigureFigure 2. (A 2.) Chemical(A) Chemical structure structure of of Aflatoxin Aflatoxin B1B1 adduct;adduct; and and (B ()B NMR) NMR structure structure of a ofDNA a DNA duplex duplex molecule;complex with the purple Aflatoxin structure B1 adduct represents (PDB the code: backbone 2KH3). of The nucleic orange acid; structure the blue representsand red atoms the insmall the complex with Aflatoxin B1 adduct (PDB code: 2KH3). The orange structure represents the small moleculemolecule; representthe purple nitrogen structure and represents oxygen atoms, the backbone respectively. of nucleic acid; the blue and red atoms in the molecule; the purple structure represents the backbone of nucleic acid;
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