Blind Dockings of Benzothiazoles to Multiple Receptor Conformations of Triosephosphate Isomerase from <i>Trypanosoma cruzi</i> and Human

Kurkcuoglu, Zeynep; Ural, Gulgun; Akten, Ebru Demet; Doruker, Pemra

doi:10.1002/minf.201100109

Cited by 11 publications

(11 citation statements)

References 41 publications

(61 reference statements)

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“…For example, we applied the same methodology with five modes to the enzyme triosephosphate isomerase (results not shown), expressing a loop closing motion (loop RMSD of 4.5 Å) over the binding site for efficient catalysis. Two cycles were sufficient to observe loop closure in the generated conformers and produce satisfactory docking results in conformity with our previous study [ 61 ].…”

Section: Discussionsupporting

confidence: 88%

Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

Kurkcuoglu

Doruker

2016

PLoS ONE

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Incorporating receptor flexibility in small ligand-protein docking still poses a challenge for proteins undergoing large conformational changes. In the absence of bound structures, sampling conformers that are accessible by apo state may facilitate docking and drug design studies. For this aim, we developed an unbiased conformational search algorithm, by integrating global modes from elastic network model, clustering and energy minimization with implicit solvation. Our dataset consists of five diverse proteins with apo to complex RMSDs 4.7–15 Å. Applying this iterative algorithm on apo structures, conformers close to the bound-state (RMSD 1.4–3.8 Å), as well as the intermediate states were generated. Dockings to a sequence of conformers consisting of a closed structure and its “parents” up to the apo were performed to compare binding poses on different states of the receptor. For two periplasmic binding proteins and biotin carboxylase that exhibit hinge-type closure of two dynamics domains, the best pose was obtained for the conformer closest to the bound structure (ligand RMSDs 1.5–2 Å). In contrast, the best pose for adenylate kinase corresponded to an intermediate state with partially closed LID domain and open NMP domain, in line with recent studies (ligand RMSD 2.9 Å). The docking of a helical peptide to calmodulin was the most challenging case due to the complexity of its 15 Å transition, for which a two-stage procedure was necessary. The technique was first applied on the extended calmodulin to generate intermediate conformers; then peptide docking and a second generation stage on the complex were performed, which in turn yielded a final peptide RMSD of 2.9 Å. Our algorithm is effective in producing conformational states based on the apo state. This study underlines the importance of such intermediate states for ligand docking to proteins undergoing large transitions.

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Section: Discussionsupporting

confidence: 88%

Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

Kurkcuoglu

Doruker

2016

PLoS ONE

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“…In this study, we found that bt10 binds to the tunnel region, which is at the edge of the interface, and its effect seems to propagate through the H-bonding network toward the active site. Moreover, in our previous blind docking study (23), 89% of bt10 poses were located in the tunnel region of the TIM dimer, whereas comparatively fewer (38%) tended to be located in the interfacial region of monomeric TIM. In view of these findings, bt10 seems to fall into the third category due to its stabilization of the dimeric structure and its allosteric effect on the active region's conformational dynamics.…”

Section: Discussionmentioning

confidence: 95%

“…Apo runs were based on the x-ray structure with Protein Data Bank (27) ID 1tcd (2) at 1.83 Å resolution. For TcTIM-bt10 complex simulations, we used bt10-docked structures from our previous docking study (23). The detailed configurations of each run are given in Table S1 in the Supporting Material.…”

Section: Simulationsmentioning

confidence: 99%

“…Previous works revealed that bt10 interacts with the aromatic clusters formed by Phe-75 of one subunit and Tyr-102/103 of the other subunit on the interface (21)(22)(23) in the tunnel region formed by dimerization. Our previous blind docking study (23) indicated that bt10 binds selectively to the tunnel region in the dimer, whereas its specificity for the interface decreases in the monomer. However, the specific inhibitory mechanism of this derivative is still not clear.…”

Section: Introductionmentioning

confidence: 99%

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How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics

Kurkcuoglu

Findik

Akten

et al. 2015

Biophysical Journal

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The tunnel region at triosephosphate isomerase (TIM)'s dimer interface, distant from its catalytic site, is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi, the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor, named bt10. Within the time frame of our MD simulations, we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10, which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54,000 MD snapshots. Using this computationally efficient technique, we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly, we observed allosteric changes in the catalytic loop's dynamics, flexibility, and correlations, as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.

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“…Besides, our procedure suggested unique alternative allosteric locations observed at the interface of monomeric subunits. Interface regions in oligomeric proteins usually accommodate potential allosteric sites as the global dynamics in complex systems is most often described by the relative rearrangement of these subunits (Kurkcuoglu et al, 2011(Kurkcuoglu et al, , 2015. Thus, a structural perturbation at the interface such as ligand binding most often disrupts the dynamic character and eventually the catalytic site.…”

Section: Introductionmentioning

confidence: 99%

Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets

Ayyildiz

Celiker

Ozhelvaci

et al. 2020

Front. Mol. Biosci.

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Three allosteric glycolytic enzymes, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase and pyruvate kinase, associated with bacterial, parasitic and human species, were explored to identify potential allosteric sites that would be used as prime targets for species-specific drug design purposes using a newly developed approach which incorporates solvent mapping, elastic network modeling, sequence and structural alignments. The majority of binding sites detected by solvent mapping overlapped with the interface regions connecting the subunits, thus appeared as promising target sites for allosteric regulation. Each binding site was then evaluated by its ability to alter the global dynamics of the receptor defined by the percentage change in the frequencies of the lowest-frequency modes most significantly and as anticipated, the most effective ones were detected in the vicinity of the well-reported catalytic and allosteric sites. Furthermore, some of our proposed regions intersected with experimentally resolved sites which are known to be critical for activity regulation, which further validated our approach. Despite the high degree of structural conservation encountered between bacterial/parasitic and human glycolytic enzymes, the majority of the newly presented allosteric sites exhibited a low degree of sequence conservation which further increased their likelihood to be used as species-specific target regions for drug design studies.

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Blind Dockings of Benzothiazoles to Multiple Receptor Conformations of Triosephosphate Isomerase from Trypanosoma cruzi and Human

Cited by 11 publications

References 41 publications

Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics

Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets

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