| 1. |
- Jacobsson, Micael, et al.
(författare)
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Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:9, s. 2777-2786
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Tidskriftsartikel (refereegranskat)abstract
- Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria. The virtual screening protocol combined 3D pharmacophore filtering, docking, and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder. The virtual screen resulted in the selection of 28 compounds that were acquired and tested from 2.6 million starting structures. Two of the seven binders were predicted to bind in the amino substrate binding pocket. Both of these showed stronger binding upon addition of methylthioadenosine, one of the two products of the enzyme, and a known binder and inhibitor. The five other compounds were predicted to bind in the part of the active site where the other substrate, decarboxylated S-adenosylmethionine, binds. These five compounds all competed for binding with methylthioadenosine.
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| 2. |
- Jacobsson, Micael, et al.
(författare)
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Improving structure-based virtual screening by multivariate analysis of scoring data
- 2003
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:26, s. 5781-5789
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Tidskriftsartikel (refereegranskat)abstract
- hree different multivariate statistical methods, PLS discriminant analysis, rule-based methods, and Bayesian classification, have been applied to multidimensional scoring data from four different target proteins: estrogen receptor alpha (ERalpha), matrix metalloprotease 3 (MMP3), factor Xa (fXa), and acetylcholine esterase (AChE). The purpose was to build classifiers able to discriminate between active and inactive compounds, given a structure-based virtual screen. Seven different scoring functions were used to generate the scoring matrices. The classifiers were compared to classical consensus scoring and single scoring functions. The classifiers show a superior performance, with rule-based methods being most effective. The precision of correctly predicting an active compound is about 90% for three of the targets and about 25% for acetylcholine esterase. On the basis of these results, a new two-stage approach is suggested for structure-based virtual screening where limited activity information is available.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Jacobsson, Micael, 1975-
(författare)
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Structure-Based Virtual Screening : New Methods and Applications in Infectious Diseases
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A drug discovery project typically starts with a pharmacological hypothesis: that the modulation of a specific molecular biological mechanism would be beneficial in the treatment of the targeted disease. In a small-molecule project, the next step is to identify hits, i.e. molecules that can effect this modulation. These hits are subsequently expanded into hit series, which are optimised with respect to pharmacodynamic and pharmacokinetic properties, through medicinal chemistry. Finally, a drug candidate is clinically developed into a new drug. This thesis concerns the use of structure-based virtual screening in the hit identification phase of drug discovery.Structure-based virtual screening involves using the known 3D structure of a target protein to predict binders, through the process of docking and scoring. Docking is the prediction of potential binding poses, and scoring is the prediction of the free energy of binding from those poses. Two new methodologies, based on post-processing of scoring results, were developed and evaluated using model systems. Both methods significantly increased the enrichment of true positives. Furthermore, correlation was observed between scores and simple molecular properties, and identified as a source of false positives in structure-based virtual screening.Two target proteins, Mycobacterium tuberculosis ribose-5-phosphate isomerase, a potential drug target in tuberculosis, and Plasmodium falciparum spermidine synthase, a potential drug target in malaria, were subjected to docking and virtual screening. Docking of substrates and products of ribose-5-phosphate isomerase led to hypotheses on the role of individual residues in the active site. Additionally, virtual screening was used to predict 48 potential inhibitors, but none was confirmed as an inhibitor or binder to the target enzyme. For spermidine synthase, structure-based virtual screening was used to predict 32 potential active-site binders. Seven of these were confirmed to bind in the active site.
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| 7. |
- Rasmussen, Magnus, et al.
(författare)
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Genome-based identification and analysis of collagen-related structural motifs in bacterial and viral proteins.
- 2003
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 278:34, s. 32313-32316
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Tidskriftsartikel (refereegranskat)abstract
- Collagens are extended trimeric proteins composed of the repetitive sequence glycine-X-Y. A (c) under bar ollagen- related (S) under bar tructural (m) under bar otif (CSM) containing glycine-X-Y repeats is also found in numerous proteins often referred to as collagen-like proteins. Little is known about CSMs in bacteria and viruses, but the occurrence of such motifs has recently been demonstrated. Moreover, bacterial CSMs form collagen-like trimers, even though these organisms cannot synthesize hydroxyproline, a critical residue for the stability of the collagen triple helix. Here we present 100 novel proteins of bacteria and viruses (including bacteriophages) containing CSMs identified by in silico analyses of genomic sequences. These CSMs differ significantly from human collagens in amino acid content and distribution; bacterial and viral CSMs have a lower proline content and a preference for proline in the X position of GXY triplets. Moreover, the CSMs identified contained more threonine than collagens, and in 17 of 53 bacterial CSMs threonine was the dominating amino acid in the Y position. Molecular modeling suggests that threonines in the Y position make direct hydrogen bonds to neighboring backbone carbonyls and thus substitute for hydroxyproline in the stabilization of the collagen-like triple-helix of bacterial CSMs. The majority of the remaining CSMs were either rich in proline or rich in charged residues. The bacterial proteins containing a CSM that could be functionally annotated were either surface structures or spore components, whereas the viral proteins generally could be annotated as structural components of the viral particle. The limited occurrence of CSMs in eubacteria and lower eukaryotes and the absence of CSMs in archaebacteria suggests that DNA encoding CSMs has been transferred horizontally, possibly from multicellular organisms to bacteria.
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| 9. |
- Russo, Francesco, et al.
(författare)
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Synthesis and evaluation of a new class of tertiary alcohol based BACE-1 inhibitors
- 2009
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 65:48, s. 10047-10059
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Tidskriftsartikel (refereegranskat)abstract
- BACE-1 has emerged as one of the best characterized targets for future Alzheimer therapy. In accordance with the successful identification of masked inhibitors of HIV-1 protease, we envisioned that tert-alcohol containing transition-state mimicking structures would also be worthwhile evaluating as BACE-1 inhibitors. Twelve novel inhibitors were prepared via synthetic routes using epoxyalcohol derivates as key intermediates. The best synthesized tert-hydroxy inhibitor exhibited a BACE-1 IC50 value of 0.38 mu M.
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| 10. |
- Stjernschantz, Eva, et al.
(författare)
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Are automated molecular dynamics simulations and binding free energy calculations realistic tools in lead optimization? : An evaluation of the linear interaction energy (LIE) method
- 2006
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 46:5, s. 1972-1983
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Tidskriftsartikel (refereegranskat)abstract
- An extensive evaluation of the linear interaction energy (LIE) method for the prediction of binding affinity of docked compounds has been performed, with an emphasis on its applicability in lead optimization. An automated setup is presented, which allows for the use of the method in an industrial setting. Calculations are performed for four realistic examples, retinoic acid receptor gamma, matrix metalloprotease 3, estrogen receptor R, and dihydrofolate reductase, focusing on different aspects of the procedure. The obtained LIE models are evaluated in terms of the root-mean-square (RMS) errors from experimental binding free energies and the ability to rank compounds appropriately. The results are compared to the best empirical scoring function, selected from a set of 10 scoring functions. In all cases, good LIE models can be obtained in terms of free-energy RMS errors, although reasonable ranking of the ligands of dihydrofolate reductase proves difficult for both the LIE method and scoring functions. For the other proteins, the LIE model results in better predictions than the best performing scoring function. These results indicate that the LIE approach, as a tool to evaluate docking results, can be a valuable asset in computational lead optimization programs.
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