Wyniki wyszukiwania

1

Molecular dynamics study of protein-ligand interactions

100%

Kriz Z., Otyepka M., Bartova I., Koca J.

Cellular and Molecular Biology Letters

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2005

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tom 10

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nr Suppl.2

2

Navigating cross-kinase selectivity space

100%

Aronov A. M., McClain B., Caron P. R., Murcko M. A.

Cellular and Molecular Biology Letters

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2005

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tom 10

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nr Suppl.2

3

Rapid non-empirical approaches for estimating relative binding free energies

100%

Mark A. E., Xu Y., Liu H., Van Gunsteren W. F.

Acta Biochimica Polonica

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1995

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tom 42

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nr 4

Rapid non-empirical methods for estimating binding free energies are reviewed. A novel approach based on the application of the free energy perturbation formula to a biased ensemble is presented. Preliminary results demonstrating the applicability of this approach in protein systems are shown and the potential of this method in structure-based drug design is discussed.

4

Possible computational filter to detect proteins associated to influenza A subtype H1N1

88%

Polanco C., Buhse T., Castanon-Gonzalez J. A., Samaniego J. L.

Acta Biochimica Polonica

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2014

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tom 61

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nr 4

5

Synthetic analogues of netropsin and distamycin-synthesis of a new pyridine and carbocyclic analogues of the pyrrolecarboxamide antitumour antibiotics

75%

Bartulewicz D., Bielawski K., Markowska A., Zwierz K., Puckowska A., Rozanski A.

Acta Biochimica Polonica

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1998

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tom 45

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nr 1

A new series of pyridine-containing analogues III-XXII of distamycin A and netropsin was investigated by the molecular mechanics technique and molecular modelling. A pyridine analogue of netropsin (VII) is described, the first compound based on molecular studies, and two carbocyclic analogues of distamycin A with an N-terminal chloro- or bromoacetyl group (VIa, VIIa) were synthesized, as well as carbocyclic analogues of netropsin (VIIIb, Xb), potential carriers of alkylating elements. The potential use of VIa, VII, VIIa, VIIIb and Xb as carriers to place into the minor groove of DNA chemical groups capable of modifying DNA, is discussed.

6

Glucosamine-6-phosphate synthase, a novel target for antifungal agents. Molecular modelling studies in drug design

75%

Wojciechowski M., Milewski S., Mazerski J., Borowski E.

Acta Biochimica Polonica

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2005

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tom 52

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nr 3

Fungal infections are a growing problem in contemporary medicine, yet only a few antifungal agents are used in clinical practice. In our laboratory we proposed the enzyme L-glutamine: D-fructose-6-phosphate amidotransferase (EC 2.6.1.16) as a new target for antifungals. The structure of this enzyme consists of two domains, N-terminal and C-terminal ones, catalysing glutamine hydrolysis and sugar-phosphate isomerisation, respectively. In our laboratory a series of potent selective inhibitors of GlcN-6-P synthase have been designed and synthesised. One group of these compounds, including the most studied N3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (FMDP), behave like glutamine analogs acting as active-site-directed inactivators, blocking the N-terminal, glutamine-binding domain of the enzyme. The second group of GlcN-6-P synthase inhibitors mimic the transition state of the reaction taking place in the C-terminal sugar isomerising domain. Surprisingly, in spite of the fact that glutamine is the source of nitrogen for a number of enzymes it turned out that the glutamine analogue FMDP and its derivatives are selective against GlcN-6-P synthase and they do not block other enzymes, even belonging to the same family of glutamine amidotransferases. Our molecular modelling studies of this phenomenon revealed that even within the family of related enzymes substantial differences may exist in the geometry of the active site. In the case of the glutamine amidotransferase family the glutamine binding site of GlcN-6-P synthase fits a different region of the glutamine conformational space than other amidotransferases. Detailed analysis of the interaction pattern for the best known, so far, inhibitor of the sugar isomerising domain, namely 2-amino-2-deoxy-d-glucitol-6-phosphate (ADGP), allowed us to suggest changes in the structure of the inhibitor that should improve the interaction pattern. The novel ligand was designed and synthesised. Biological experiments confirmed our predictions. The new compound named ADMP is a much better inhibitor of glucosamine-6-phosphate synthase than ADGP.

7

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Docking for drug interface residues of modelled VPS33B of human with PtpA of Mycobacterium tuberculosis CDC1551

63%

Reddy K. M., Pattathil M. D., Jayachandra S. Y., Parameshwar A., Sulochana M. B.

International Letters of Natural Sciences

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2014

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tom 11

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nr 2

VPS33B, a human Vacuolar Protein Sorting (VPS) protein which mediates the phagolysosomal fusion in macrophage of the eukaryotic organisms. This protein has a great role during the mycobacterial infections, which binds with the Mycobacterium protein tyrosine phosphatase A (PtpA). A single functional domain of PtpA has been identified using SMART domain databases, followed by finding the antigenicity of PtpA using CLC main workbench tool. The protein-protein interaction network predicts the interface of biological functions of proteins, built by using Cytoscape 2.8.3 version tool for manual literature survey of protein sets. According to the literature the specific interactivity of PtpA with VPS33B of human lead to pathogenesis, and provided a good platform to find the structure of VPS33B as it lacks the 3 dimensional structure in PDB. Homology Modelling of VPS33B provides a significant properties to design a specific drug through screening the drug databases (eDrug3D). The modelled protein has been validated through SAVES server maintained by NIH and UCLA with the standard Ramachandran plot with accuracy of 90.7 %. From our findings the interface residues are very crucial points which has been found through docking the modelled protein and Mycobacterium protein and interface residues were selected manually using PyMol software.

8

Modelling of active forms of protein kinases: p38 - a case study

63%

Ginalski K., Lesyng B., Sowadski J., Wojciechowski M.

Acta Biochimica Polonica

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1997

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tom 44

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nr 3

An active form of p38 protein kinase, belonging to the mitogen-activated protein kinases subfamily, has been designed based on crystallographically known structures of two other kinases, an active form of protein kinase A (PKA) and an inactive form of extracellular signal-regulated kinase 2 (ERK2). The modelling procedure is described. Its general scheme can also be applied to other kinases. The structure of the active forms of p38 and PKA is very similar in the region which binds the substrate. The ATP-binding mode is very similar in the active forms of all the three studied kinases. Models of the active forms allow for further studies on transphosphorylation processes at the molecular level, and modelling of inhibitors competitive with ATP and/or substrates.

9

Structural aspects of the inhibition and catalytic mechanism of thymidylate synthase

63%

Hardy L. W.

Acta Biochimica Polonica

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1995

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tom 42

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nr 4

Thymidylate synthase (TS) is a target for anticancer drugs, due to its unique role in the biosynthesis of an essential DNA precursor. The X-ray structures available for several bacterial enzymes have been used to design novel inhibitors of TS, to structurally analyze the binding mode of existing inhibitors, and to propose catalytic roles for amino-acid residues on the protein. The first part of this paper describes some aspects of structure-based drug design, including a recent result from the groups of Montfort and Maley emphasizing the importance of conformational changes in inhibitor binding. The second part of the paper describes the work of the author on the TS mechanism, especially the catalytic roles of active site amino acids Asnl77 and Glu58 in TS from Escherichia coli. An important function for Glu58 is proposed to be preventing the excessive stabilization of a covalent intermediate. The use of isotope effects to probe the mechanistic basis for stimulation of E. coli TS by magnesium ions, and to identify differences between the E. coli and human enzymes, is described. The hypothesis that N5 of tetrahydrofolate provides the basicity for deprotonation of the nucleotide is also discussed.

Ograniczanie wyników

Molecular dynamics study of protein-ligand interactions

Navigating cross-kinase selectivity space

Rapid non-empirical approaches for estimating relative binding free energies

Possible computational filter to detect proteins associated to influenza A subtype H1N1

Synthetic analogues of netropsin and distamycin-synthesis of a new pyridine and carbocyclic analogues of the pyrrolecarboxamide antitumour antibiotics

Glucosamine-6-phosphate synthase, a novel target for antifungal agents. Molecular modelling studies in drug design

Docking for drug interface residues of modelled VPS33B of human with PtpA of Mycobacterium tuberculosis CDC1551

Modelling of active forms of protein kinases: p38 - a case study

Structural aspects of the inhibition and catalytic mechanism of thymidylate synthase