Chemical and structural biology of nucleic acids and protein-nucleic acid complexes for novel drug discovery

Gan, Jianhua; Sheng, Jia; Huang, Zhen

doi:10.1007/s11426-010-4174-x

Cited by 12 publications

(8 citation statements)

References 171 publications

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“…Our results indicate the convenience and advantage of this novel warming-up strategy in the detritylation and modified nucleic acid synthesis for nucleic acid drug discovery. [23–25] …”

Section: Resultsmentioning

confidence: 99%

Mild Detritylation of Nucleic Acid Hydroxyl Groups by Warming Up

Saloň

Zhang

Huang

2011

Nucleosides, Nucleotides and Nucleic Acids

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It is challenging to effectively deprotect hydroxyl groups of acid-or-base sensitive bio-macromolecules without causing even minor defects and compromising high quality of final products. We report here a mild detritylation strategy in mildly acidic buffers to remove the DMTr protection from the 5’-hydroxyl groups of synthetic nucleic acids. The DMTr-groups can be easily and effectively removed at pH 4.5 or 5.0 with slight warming-up (40 °C), offering virtually quantitative deprotection. This warming-up strategy is particularly useful for deprotection of the modified nucleic acids that are sensitive to the conventional acid deprotection. As a first step towards our long-term goal of synthesizing defect-free nucleic acids, our novel and simple strategy further increases the quality of synthetic nucleic acids.

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“…Our results indicate the convenience and advantage of this novel warming-up strategy in the detritylation and modified nucleic acid synthesis for nucleic acid drug discovery. [23–25] …”

Section: Resultsmentioning

confidence: 99%

Mild Detritylation of Nucleic Acid Hydroxyl Groups by Warming Up

Saloň

Zhang

Huang

2011

Nucleosides, Nucleotides and Nucleic Acids

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“…Since DNA play very important roles in cells, they are molecular targets of many clinically used drugs, such as anticancer drugs and antibiotics [2]. Study on the protein-DNA interactions would be meaningful for drugs design on the nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

Use of Amino Acid-Nucleotide Base Pair Potentials in Screening Protein-DNA Docked Complexes

Liu¹,

Chang²,

Chen³

et al. 2013

IJBBB

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Abstract-Amino acid-nucleotide base pair potentials are used to screen docked complexes generated by DOT. The pair potential algorithm designed in this paper is applied to screening 10 systems selected from protein-DNA benchmark set. For all the systems, a correct docking was placed within the top 6% of the pair potential score ranked complexes. Also, over 60% correct answers rank in the top 10% of the docked results for most of the systems.Index Terms-Amino acid-nucleotide base pair potentials, protein-DNA dock, screening. I. INTRODUCTIONProtein-DNA interactions regulate many cellular processes involving gene expression, DNA replication and repair [1]. Since DNA play very important roles in cells, they are molecular targets of many clinically used drugs, such as anticancer drugs and antibiotics [2]. Study on the protein-DNA interactions would be meaningful for drugs design on the nucleic acids. However, the determination of the protein-DNA structure is still difficult through the biochemistry experiment directly. Until January 5, 2013, there are over 87,000 structures deposited in the PDB (Protein Data Bank) [3], where the number of protein-NA structure is just almost 4,000. Hence, computational techniques such as protein-DNA docking will become an increasingly important way to help understand the molecular mechanisms of biological systems [4].Although a number of approaches are available for predicting the docking of protein-protein, the treatment of docking of small ligands and proteins with other proteins, the treatment of the docking of nucleic acids onto proteins lags far behind [5]. Two particular problems have hampered the development of efficient docking methods: the sparsity of the information to define the DNA-binding interface and the inherent flexibility of DNA [6]. Nonetheless, study groups such as Takeda et al. [7] and Liu et al. [8] have already made achievements on modeling protein-DNA interactions using different computational methods. However, these treatments have never applied amino acid-nucleotide base pair potentials on the docking of protein-DNA even if empirical residue-residue pair potentials [9]-[11] have already played an important role in protein-protein dockings for a long time. II. MATERIALS AND METHODS A. The Program DOTThe program DOT [12], which uses the sum of both a Poisson-Boltzmann electrostatic energy and a van der Waals energy as its energy function, quickly finds low-energy docked structure for two macromolecules by performing a systematic search over six degrees of freedom. A major objective of the DOT program is to provide a method that is fast enough for routine use and cheap enough to be used in highly speculative modes.In our earlier work, we applied DOT to dock 10 systems selected from protein-DNA benchmark set [13] and the results showed DOT was able to produce correct answers efficiently. However, these results were not ranking forward enough to guide the design of experiments to test the suggested interactions. Hence, amino acid-nucleotide base pair potentials w...

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“…Furthermore, selenium is considered as an ideal anomalous scattering center in X-ray crystal diffraction due to its K edge (0.9795 Å). The Se anomalous signal for multiple-wavelength anomalous dispersion (MAD) and single-wavelength anomalous dispersion (SAD) has significantly facilitated crystallographic studies on biological macromolecules [3]. The successful seleno-methionine MAD technique and its application in structural determination of proteins have been developed for over 20 years [4].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel di-Se-containing thymidine and Se-DNAs for structure and function studies

Abdalla

Huang

2012

Sci. China Chem.

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The selenium derivatization of nucleic acids and nucleic acid-protein complexes has provided a powerful tool to solve phase problem in X-ray crystallography. Selenium atoms in the nucleotides can serve as fine scattering centers in crystal diffraction. Towards the synthesis of multiple selenium atom-containing nucleotides, which offers strong phasing power to facilitate crystal structure determination, we report here the synthesis of the thymidine analogue containing two Se atoms in one nucleobase. The novel Se-containing nucleoside and oligonucleotide DNAs were synthesized and found with the red-shifted UV spectrum and yellow color. Their unique properties are useful in phase determination, nucleic acid-based detection as well as spectroscopic studies of nucleic acids and nucleic acid-protein complexes.

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Chemical and structural biology of nucleic acids and protein-nucleic acid complexes for novel drug discovery

Cited by 12 publications

References 171 publications

Mild Detritylation of Nucleic Acid Hydroxyl Groups by Warming Up

Mild Detritylation of Nucleic Acid Hydroxyl Groups by Warming Up

Use of Amino Acid-Nucleotide Base Pair Potentials in Screening Protein-DNA Docked Complexes

Synthesis of novel di-Se-containing thymidine and Se-DNAs for structure and function studies

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