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

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.

2019 ◽  
Vol 10 (19) ◽  
pp. 5064-5072 ◽  
Author(s):  
Kaspar Zimmermann ◽  
Daniel Joss ◽  
Thomas Müntener ◽  
Elisa S. Nogueira ◽  
Marc Schäfer ◽  
...  

Unraveling the native structure of protein–ligand complexes in solution enables rational drug design.


Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1578 ◽  
Author(s):  
Guanhui Wu ◽  
Luying Chen ◽  
Wenting Liu ◽  
Danzhou Yang

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.


2021 ◽  
Vol 7 ◽  
Author(s):  
Arun S. Konagurthu ◽  
Ramanan Subramanian ◽  
Lloyd Allison ◽  
David Abramson ◽  
Peter J. Stuckey ◽  
...  

What is the architectural “basis set” of the observed universe of protein structures? Using information-theoretic inference, we answer this question with a dictionary of 1,493 substructures—called concepts—typically at a subdomain level, based on an unbiased subset of known protein structures. Each concept represents a topologically conserved assembly of helices and strands that make contact. Any protein structure can be dissected into instances of concepts from this dictionary. We dissected the Protein Data Bank and completely inventoried all the concept instances. This yields many insights, including correlations between concepts and catalytic activities or binding sites, useful for rational drug design; local amino-acid sequence–structure correlations, useful for ab initio structure prediction methods; and information supporting the recognition and exploration of evolutionary relationships, useful for structural studies. An interactive site, Proçodic, at http://lcb.infotech.monash.edu.au/prosodic (click), provides access to and navigation of the entire dictionary of concepts and their usages, and all associated information. This report is part of a continuing programme with the goal of elucidating fundamental principles of protein architecture, in the spirit of the work of Cyrus Chothia.


2013 ◽  
Vol 21 (6) ◽  
pp. 1431-1436 ◽  
Author(s):  
Vaida Jogaitė ◽  
Asta Zubrienė ◽  
Vilma Michailovienė ◽  
Joana Gylytė ◽  
Vaida Morkūnaitė ◽  
...  

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