scholarly journals Solution Structure of a 2:1 Quindoline–c-MYC G-Quadruplex: Insights into G-Quadruplex-Interactive Small Molecule Drug Design

2011 ◽  
Vol 133 (44) ◽  
pp. 17673-17680 ◽  
Author(s):  
Jixun Dai ◽  
Megan Carver ◽  
Laurence H. Hurley ◽  
Danzhou Yang
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Solution Structure ◽  
Small Molecule Drug ◽  
G Quadruplex

scholarly journals Overlapping but distinct: a new model for G-quadruplex biochemical specificity

2021 ◽  
Author(s):  
Martin Volek ◽  
Sofia Kolesnikova ◽  
Katerina Svehlova ◽  
Pavel Srb ◽  
Ráchel Sgallová ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Drug Design ◽  
Solution Structure ◽  
Biochemical Data ◽  
Biological Regulation ◽  
New Model ◽  
G Quadruplex ◽  
Range Of Functions ◽  
Nucleic Acid Structures ◽  
Sequence Requirements

Abstract G-quadruplexes are noncanonical nucleic acid structures formed by stacked guanine tetrads. They are capable of a range of functions and thought to play widespread biological roles. This diversity raises an important question: what determines the biochemical specificity of G-quadruplex structures? The answer is particularly important from the perspective of biological regulation because genomes can contain hundreds of thousands of G-quadruplexes with a range of functions. Here we analyze the specificity of each sequence in a 496-member library of variants of a reference G-quadruplex with respect to five functions. Our analysis shows that the sequence requirements of G-quadruplexes with these functions are different from one another, with some mutations altering biochemical specificity by orders of magnitude. Mutations in tetrads have larger effects than mutations in loops, and changes in specificity are correlated with changes in multimeric state. To complement our biochemical data we determined the solution structure of a monomeric G-quadruplex from the library. The stacked and accessible tetrads rationalize why monomers tend to promote a model peroxidase reaction and generate fluorescence. Our experiments support a model in which the sequence requirements of G-quadruplexes with different functions are overlapping but distinct. This has implications for biological regulation, bioinformatics, and drug design.

scholarly journals Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1578 ◽  
Author(s):  
Guanhui Wu ◽  
Luying Chen ◽  
Wenting Liu ◽  
Danzhou Yang
Keyword(s):  
Small Molecule ◽  
Solution Structure ◽  
Structural Information ◽  
Rational Drug Design ◽  
Hybrid Type ◽  
G4 Dna ◽  
Rational Drug ◽  
G Quadruplex ◽  
Molecule Recognition ◽  
Dna Secondary Structures

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

Synthetic Small Molecules Targeting G-Quadruplexes and their Application

2015 ◽  
Vol 1088 ◽  
pp. 507-513
Author(s):  
Hui Yu ◽  
Yan Li Wang ◽  
Xiao Yin Zhao ◽  
Wen Zhang
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Mode ◽  
Current Understanding ◽  
Promising Target ◽  
G Quadruplex ◽  
Small Molecule Ligands

G-quadruplex is expected to be a promising target for drug design. The manually synthesized small-molecule compounds are able to induce the formation of and stabilize G-quadruplexes. In this paper, we summarize the current understanding of the structure of G-quadruplexes, the binding mode of G-quadruplexes and small-molecule ligands, and important synthesized small molecules targeting G-quadruplexes as potential drugs.

ChemInform Abstract: Kinase Domain Mutations in Cancer: Implications for Small Molecule Drug Design Strategies

ChemInform ◽  
2009 ◽  
Vol 40 (26) ◽  
Author(s):  
Jack A. Bikker ◽  
Natasja Brooijmans ◽  
Allan Wissner ◽  
Tarek S. Mansour
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Kinase Domain ◽  
Design Strategies ◽  
Small Molecule Drug ◽  
Kinase Domain Mutations

Kinase Domain Mutations in Cancer: Implications for Small Molecule Drug Design Strategies

2009 ◽  
Vol 52 (6) ◽  
pp. 1493-1509 ◽  
Author(s):  
Jack A. Bikker ◽  
Natasja Brooijmans ◽  
Allan Wissner ◽  
Tarek S. Mansour
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Kinase Domain ◽  
Design Strategies ◽  
Small Molecule Drug ◽  
Kinase Domain Mutations

Strategies to identify ligands for orphan G-protein-coupled receptors

2002 ◽  
Vol 30 (4) ◽  
pp. 789-793 ◽  
Author(s):  
G. Milligan
Keyword(s):  
Drug Design ◽  
G Protein ◽  
Small Molecule ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Protein Targets ◽  
Small Molecule Drug ◽  
Natural Ligands ◽  
G Protein Coupled

G-protein-coupled receptors are the most tractable class of protein targets for small molecule drug design. Sequencing of the human genome allied to bio-informatic analysis has identified a large number of putative receptors for which the natural ligands remain undefined. A range of currently employed and developing strategies to identify ligands that interact with these orphan receptors and to validate them as drug targets are described and discussed.

Small molecule drug conjugates (SMDCs): an emerging strategy for anticancer drug design and discovery

2021 ◽  
Vol 45 (12) ◽  
pp. 5291-5321
Author(s):  
Tarun Kumar Patel ◽  
Nilanjan Adhikari ◽  
Sk. Abdul Amin ◽  
Swati Biswas ◽  
Tarun Jha ◽  
...  
Keyword(s):  
Drug Design ◽  
Anticancer Drug ◽  
Small Molecule ◽  
Chemotherapeutic Agents ◽  
Drug Molecule ◽  
Lysosomal Ph ◽  
Small Molecule Drug ◽  
Drug Conjugates ◽  
Small Molecule Drugs ◽  
Tumor Environment

Mechanisms of how SMDCs work. Small molecule drugs are conjugated with the targeted ligand using pH sensitive linkers which allow the drug molecule to get released at lower lysosomal pH. It helps to accumulate the chemotherapeutic agents to be localized in the tumor environment upon cleaving of the pH-labile bonds.

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