scholarly journals Molecular Dynamics Simulations of Bromodomains Reveal Binding-Site Flexibility and Multiple Binding Modes of the Natural Ligand Acetyl-Lysine

2014 ◽  
Vol 54 (8-9) ◽  
pp. 1084-1092 ◽  
Author(s):  
Dimitrios Spiliotopoulos ◽  
Amedeo Caflisch
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Binding Modes ◽  
Natural Ligand ◽  
Multiple Binding ◽  
Dynamics Simulations

Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana

2020 ◽  
Vol 16 (6) ◽  
pp. 784-795
Author(s):  
Krisnna M.A. Alves ◽  
Fábio José Bonfim Cardoso ◽  
Kathia M. Honorio ◽  
Fábio A. de Molfetta
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Point Of View ◽  
New Drugs ◽  
Leishmania Mexicana ◽  
Receptor Complexes ◽  
Starting Point ◽  
Dynamics Simulations ◽  
Selection Of

Background:: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. Objective:: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). Methods: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. Results:: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. Conclusion:: he use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.

scholarly journals The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1250
Author(s):  
Hien T. T. Lai ◽  
Alejandro Giorgetti ◽  
Giulia Rossetti ◽  
Toan T. Nguyen ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Transmembrane Protein ◽  
Free Form ◽  
Experimental Investigations ◽  
Terminal Part ◽  
Dynamics Simulations ◽  
Cholesterol Binding

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

Effects of Arginine on Multimodal Chromatography: Experiments and Simulations

2018 ◽  
Vol 20 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Atsushi Hirano ◽  
Kentaro Shiraki ◽  
Tomoshi Kameda
Keyword(s):  
Molecular Dynamics ◽  
Mixed Mode ◽  
Binding Modes ◽  
Aromatic Residues ◽  
Multimodal Chromatography ◽  
Cationic Resin ◽  
Multiple Binding ◽  
Guanidinium Group ◽  
Dynamics Simulations ◽  
Protein Denaturant

Multimodal or mixed-mode chromatography can be used to separate various proteins, including antibodies. The separation quality and efficiency have been improved by the addition of solutes, especially arginine. This review summarizes the mechanism underlying the effects of arginine on protein elution in multimodal chromatography with neutral, anionic or cationic resin ligands; the mechanism has been investigated using experiments and molecular dynamics simulations. Arginine is effective in facilitating protein elution compared to salts and protein denaturants such as guanidine and urea. The unique elution effect of arginine can be explained by the interplay among arginine, proteins and the resin ligands. Arginine exhibits multiple binding modes for the ligands and further affinity for protein aromatic residues through its guanidinium group. These properties make arginine versatile for protein elution in multimodal chromatography. Taking into account that arginine is an aggregation suppressor for proteins but not a protein denaturant, arginine is a promising protein-eluting reagent for multimodal chromatography.

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