scholarly journals DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

F1000Research ◽  
2016 ◽  
Vol 3 ◽  
pp. 262
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Conformational Changes ◽  
Protein Docking ◽  
Target Protein ◽  
Current Work ◽  
Homologous Proteins ◽  
Contact Points ◽  
Enzymatic Function ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Target Enzyme

The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already ’plastic’ binding site. Thus, DOCLASP presents a method for ’soft docking’ ligands to proteins with low computational requirements.

scholarly journals DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 262 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Bacillus Cereus ◽  
Phospholipase C ◽  
Protein Docking ◽  
Target Protein ◽  
Current Work ◽  
Side Chain ◽  
Contact Points ◽  
Enzymatic Function ◽  
Target Enzyme

The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are no significant matches, the ligand cannot be docked in the protein. Otherwise, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. This provides the docked ligand in the target enzyme. Previously, CLASP was used to predict and validate (in vivo) the inhibition of phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus by two dipeptidyl peptidase-IV (DPP4) inhibitors - vildagliptin and K-579. In the current work, vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. The docked ligand is free from steric clashes and interacts with the same side chain residues that bind myo-inositol, providing corroboration of the validity of the proposed methodology.

scholarly journals DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 262 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Bacillus Cereus ◽  
Phospholipase C ◽  
Protein Docking ◽  
Target Protein ◽  
Current Work ◽  
Side Chain ◽  
Contact Points ◽  
Enzymatic Function ◽  
Target Enzyme

The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are no significant matches, the ligand cannot be docked in the protein. Otherwise, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. This provides the docked ligand in the target enzyme. Previously, CLASP was used to predict and validate (in vivo) the inhibition of phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus by two dipeptidyl peptidase-IV (DPP4) inhibitors - vildagliptin and K-579. In the current work, vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. The docked ligand is free from steric clashes and interacts with the same side chain residues that bind myo-inositol, providing corroboration of the validity of the proposed methodology.

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

Effects of Multiple Binding Sites on Studies of Hydrogen Bonding between Nitroxide Radicals and Solvent Molecules

1993 ◽  
Vol 58 (1) ◽  
pp. 47-52 ◽  
Author(s):  
Imad Al-Bala'a ◽  
Richard D. Bates
Keyword(s):  
Hydrogen Bonding ◽  
Magnetic Resonance ◽  
Binding Site ◽  
Binding Sites ◽  
Hyperfine Coupling Constant ◽  
Hydrogen Donor ◽  
Complex Formation Constants ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Solvent Molecules

The role of more than one binding site on a nitroxide free radical in magnetic resonance determinations of the properties of the complex formed with a hydrogen donor is examined. The expression that relates observed hyperfine couplings in EPR spectra to complex formation constants and concentrations of each species in solution becomes much more complex when multiple binding sites are present, but reduces to a simpler form when binding at the two sites occurs independently and the binding at the non-nitroxide site does not produce significant differences in the hyperfine coupling constant in the complexed radical. Effects on studies of hydrogen bonding between multiple binding site nitroxides and hydrogen donor solvent molecules by other magnetic resonance methods are potentially more extreme.

scholarly journals Cryo-EM structure of human Wntless in complex with Wnt3a

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing Zhong ◽  
Yanyu Zhao ◽  
Fangfei Ye ◽  
Zaiyu Xiao ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Multiple Interfaces ◽  
Wnt Proteins ◽  
Binding Partners ◽  
Multiple Binding Sites ◽  
Evolutionarily Conserved ◽  
Multiple Binding ◽  
Hydrophobic Tunnel ◽  
Conserved Core

AbstractWntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.

scholarly journals Heparan sulfate and heparin interactions with proteins

2015 ◽  
Vol 12 (110) ◽  
pp. 20150589 ◽  
Author(s):  
Maria C. Z. Meneghetti ◽  
Ashley J. Hughes ◽  
Timothy R. Rudd ◽  
Helena B. Nader ◽  
Andrew K. Powell ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Ex Vivo ◽  
Sequence Specificity ◽  
Structure Activity ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Heparin Activity

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro , ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure–activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure–activity relationships and regulation will be discussed.

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