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.

Enzyme regulation by biological disulfides

1989 ◽  
Vol 9 (5) ◽  
pp. 593-604 ◽  
Author(s):  
Raul N. Ondarza
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Regulatory Mechanism ◽  
Enzyme Regulation ◽  
Rational Drug Design ◽  
Host Cells ◽  
Disulfide Exchange ◽  
Rational Drug

More than a dozen enzymes have been found to be activated or inhibited in vitro by disulfide-exchange between the protein and small-molecule disulfides. Accordingly, thiol/disulfide ratio changes in vivo may be of great importance in the regulation of cellular metabolism. An awareness of this regulatory mechanism in both host cells and parasites, coupled with information on the presence or absence of key enzymes, may lead to rational drug design against certain diseases involving thiol intermediates, including trypanosomiasis.

scholarly journals Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

2020 ◽  
Vol 21 (15) ◽  
pp. 5262 ◽  
Author(s):  
Qingxin Li ◽  
CongBao Kang
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Structural Biology ◽  
Small Molecule ◽  
Molecular Interactions ◽  
Mechanisms Of Action ◽  
Rational Drug Design ◽  
Binding Modes ◽  
Small Molecule Drugs ◽  
Rational Drug

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

Blind Man’s Bluff – Elaboration of Fragment Hits in the Absence of Structure for the Development of Antitrypsin Deficiency Inhibitors

2013 ◽  
Vol 66 (12) ◽  
pp. 1525 ◽  
Author(s):  
Stephen J. Headey ◽  
Mary C. Pearce ◽  
Martin J. Scanlon ◽  
Stephen P. Bottomley
Keyword(s):  
Nmr Spectroscopy ◽  
Protein Binding ◽  
Protein Misfolding ◽  
Structural Information ◽  
Rational Drug Design ◽  
Information Need ◽  
X Ray Crystallography ◽  
Rational Drug ◽  
Fragment Library ◽  
Antitrypsin Deficiency

The three pillars of rational drug design from a fragment library are an efficient screen, a robust assay, and atomic-resolution structures of the protein–ligand complexes. However, not all targets are amenable to structure determination by X-ray crystallography or NMR spectroscopy. In particular, targets involved in diseases of protein misfolding are inherently intractable. In the absence of structures, we are blind. However, the lack of structural information need not preclude the use of fragment-based approaches. The use of appropriate NMR techniques can enable us to detect the effects of protein binding on ligand resonances. In our efforts to identify compounds that affect the kinetics of α1-antitrypsin misfolding, we have used saturation transfer difference NMR spectroscopy to detect hits from mixtures of compounds in a fragment library. In the absence of structures, the initial challenge is three-fold: to (1) distinguish between binding sites; (2) evaluate the relative affinities of hits; and (3) advance them to the stage where activity can be detected in biological assays. We largely achieved these aims by the use of Carr–Purcell–Meiboom–Gill NMR competition experiments that detect differential relaxation of the ligand on protein binding.

scholarly journals Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

2021 ◽  
Vol 14 (12) ◽  
pp. 1303
Author(s):  
Jesús Borrego ◽  
Adam Feher ◽  
Norbert Jost ◽  
Gyorgy Panyi ◽  
Zoltan Varga ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Amino Acid Sequences ◽  
Rational Drug Design ◽  
Drug Candidate ◽  
In Silico Docking ◽  
Rational Drug ◽  
Wide Range ◽  
Potential Therapeutic Application

The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.

scholarly journals Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4412 ◽  
Author(s):  
Alexey Smirnov ◽  
Asta Zubrienė ◽  
Elena Manakova ◽  
Saulius Gražulis ◽  
Daumantas Matulis
Keyword(s):  
Carbonic Anhydrase ◽  
Structural Information ◽  
Hydrophobic Effect ◽  
Rational Drug Design ◽  
Inhibitor Binding ◽  
Binding Thermodynamics ◽  
Chemical Structures ◽  
Structure Correlations ◽  
Rational Drug ◽  
Human Carbonic Anhydrase

The structure-thermodynamics correlation analysis was performed for a series of fluorine- and chlorine-substituted benzenesulfonamide inhibitors binding to several human carbonic anhydrase (CA) isoforms. The total of 24 crystal structures of 16 inhibitors bound to isoforms CA I, CA II, CA XII, and CA XIII provided the structural information of selective recognition between a compound and CA isoform. The binding thermodynamics of all structures was determined by the analysis of binding-linked protonation events, yielding the intrinsic parameters, i.e., the enthalpy, entropy, and Gibbs energy of binding. Inhibitor binding was compared within structurally similar pairs that differ bypara-ormeta-substituents enabling to obtain the contributing energies of ligand fragments. The pairs were divided into two groups. First,similarbinders—the pairs that keep the same orientation of the benzene ring exhibited classical hydrophobic effect, a less exothermic enthalpy and a more favorable entropy upon addition of the hydrophobic fragments. Second,dissimilarbinders—the pairs of binders that demonstrated altered positions of the benzene rings exhibited the non-classical hydrophobic effect, a more favorable enthalpy and variable entropy contribution. A deeper understanding of the energies contributing to the protein-ligand recognition should lead toward the eventual goal of rational drug design where chemical structures of ligands could be designed based on the target protein structure.

A nanobiosensor for the simple detection of small molecules using non-crosslinking aggregation of gold nanoparticles with G-quadruplexes

2020 ◽  
Vol 12 (3) ◽  
pp. 230-238
Author(s):  
Surachada Chuaychob ◽  
Chongdee Thammakhet-Buranachai ◽  
Proespichaya Kanatharana ◽  
Panote Thavarungkul ◽  
Chittanon Buranachai ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Small Molecules ◽  
Small Molecule ◽  
Colorimetric Sensor ◽  
G4 Dna ◽  
G Quadruplex ◽  
Simple Detection

This work demonstrates a simple and specific colorimetric sensor for a hazardous small molecule, cisplatin, using a G-quadruplex (G4) DNA as a sensing probe and non-crosslinking aggregation of gold nanoparticles (AuNPs) as a signal enhancer.

Sign in / Sign up

Export Citation Format

Share Document