Molecular dynamics simulations of Zika virus NS3 helicase: Insights into RNA binding site activity

2017 ◽  
Vol 492 (4) ◽  
pp. 643-651 ◽  
Author(s):  
Melina Mottin ◽  
Rodolpho C. Braga ◽  
Roosevelt A. da Silva ◽  
Joao H. Martins da Silva ◽  
Alexander L. Perryman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Zika Virus ◽  
Rna 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.

scholarly journals Molecular Dynamics Simulations of A27S and K120A Mutated PTP1B Reveals Selective Binding of the Bidentate Inhibitor

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Xi Chen ◽  
Xia Liu ◽  
Qiang Gan ◽  
Changgen Feng ◽  
Qian Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Tyrosine Phosphatase ◽  
Selective Binding ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Dynamics Simulations

Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.

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