Rebecca Wade

Multidisciplinary development of selective anti-parasitic multi-target inhibitors of PTR1/DHFR based on a pteridine scaffold.

Computational prediction of physicochemical and advanced descriptors related to ADME-Tox and PAINS assessment. Potential correlations of the computed descriptors with experimentally determined anti-parasitic activities and correlations between experimentally determined levels of target protein inhibition (PTR1, DHFR) with the anti-parasitic activity were also studied.

Rigid-body docking studies and induced-fit docking studies of pteridine-based compounds to the target proteins TbPTR1, TbDHFR, LmPTR1, LmDHFR and the off-target hDHFR. For both PTR1 variants and human DHFR, conserved structural water sets were considered. Preparations of compound libraries and docking receptors are also covered.

Docking results of pteridine-based compounds in different target PTR1 and DHFR receptors and the off-target human DHFR when treating ligands as flexible and the protein receptors as a rigid-body.

Docking results of pteridine-based compounds in different target PTR1 and DHFR receptors and the off-target human DHFR when using an induced fit docking routine with an initial crude ligand placement step, subsequent receptor optimization in response to ligand binding and another docking step into the optimized receptor.

Computational prediction of physicochemical and advanced descriptors related to ADME-Tox.

Assessment of possible linear correlations between predicted ADMET descriptors from QikProp (Schrödinger, LLC, New York, NY) runs and experimentally determined activities against T. brucei brucei bloodstream forms with the help of a Python script.

Assessment of the possible multiple correlation between experimentally determined TbPTR1 and TbDHFR inhibition values and corresponding anti-parasitic activities against T. brucei brucei bloodstream forms using a Python script.

In silico check and filtering for potential Pan-assay interference compounds.

Compound data, library construction schemes and preparation routine for small drug-like molecules as ligands in docking and for further analysis.

Prepared target (parasite PTR1, DHFR) and off-target (human DHFR) protein receptors for docking studies, in part with conserved structural water sets, and the corresponding preparation routine.

Zip-archive with induced fit docking results for reference compounds methotrexate, 1 and 2 as well as the N10-modified compound 4 in their neutral and N1-protonated variants and the N10-modified compound 3 and Tail-modified compounds 14, 16, 17 and 26 in neutral form as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The LmPTR1 receptor was based on PDB-ID 1e92 without additional water molecules. Docking results were obtained by Induced Fit
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Zip-archive with induced fit docking results for reference compounds methotrexate and 1 as well as the N10-modified compounds 3 and 4 in their neutral and N1-protonated variants and the N10-modified compound 9 and merged-series compound 19 in neutral form as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The TbPTR1 receptor was based on PDB-ID 2x9g with explicit conserved structural water molecules. Docking results were obtained by Induced
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Zip-archive with induced fit docking results for reference compounds methotrexate and 1 as well as the N10-modified compounds 3 and 4 in their neutral and N1-protonated variants and the PABA-modified compound 27 in neutral form as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The TbPTR1 receptor was based on PDB-ID 2x9g without additional water molecules. Docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime
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Zip-archive with results for reference and all designed pteridines in their neutral and N1-protonated variant as multi-model PDB files, ordered as ranked by Glide docking scores, in the LmPTR1 receptor based on PDB-ID 1e92 with explicit conserved structural water molecules. Docking results obtained by rigid-body XP docking with Schrödinger Glide (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Glide v6.9). For further details and naming conventions also refer to the README file.
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Zip-archive with results for reference and all designed pteridines in their neutral and N1-protonated variant as multi-model PDB files, ordered as ranked by Glide docking scores, in the LmPTR1 receptor based on PDB-ID 1e92 without explicit water molecules. Docking results obtained by rigid-body XP docking with Schrödinger Glide (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Glide v6.9). For further details and naming conventions also refer to the README file.

Zip-archive with results for reference and all designed pteridines in their neutral and N1-protonated variant as multi-model PDB files, ordered as ranked by Glide docking scores, in the TbDHFR receptor based on PDB-ID 3rg9 without explicit water molecules. Docking results obtained by rigid-body XP docking with Schrödinger Glide (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Glide v6.9). For further details and naming conventions also refer to the README file.

Zip-archive with results for reference and all designed pteridines in their neutral and N1-protonated variant as multi-model PDB files, ordered as ranked by Glide docking scores, in the TbPTR1 receptor based on PDB-ID 2x9g with explicit conserved structural water molecules. Docking results obtained by rigid-body XP docking with Schrödinger Glide (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Glide v6.9). For further details and naming conventions also refer to the README file.
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Zip-archive with results for reference and all designed pteridines in their neutral and N1-protonated variant as multi-model PDB files, ordered as ranked by Glide docking scores, in the TbPTR1 receptor based on PDB-ID 2x9g without explicit water molecules. Docking results obtained by rigid-body XP docking with Schrödinger Glide (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Glide v6.9). For further details and naming conventions also refer to the README file.

Zip-archive with induced fit docking results for methotrexate in its neutral and N1-protonated variant as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The hDHFR receptor was based on PDB-ID 1u72 with explicit conserved structural water molecules. Docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Induced
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Zip-archive with induced fit docking results for methotrexate in its neutral and N1-protonated variant as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The hDHFR receptor was based on PDB-ID 1u72 without additional water molecules. Docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Induced Fit Docking
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Zip-archive with induced fit docking results for methotrexate in its neutral and N1-protonated variant as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The LmDHFR receptor was based on a published homology model of LmDHFR (Panecka-Hofman et al. (2017) Biochim Biophys Acta Gen Subj. 1861(12), 3215-3230. DOI: 10.1016/j.bbagen.2017.09.012) without additional water molecules. Docking results were obtained by Induced Fit docking with Schrödinger
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Zip-archive with induced fit docking results for methotrexate in its neutral and N1-protonated variant as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The TbDHFR receptor was based on PDB-ID 3rg9 without additional water molecules. Docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Induced Fit Docking
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Zip-archive with induced fit docking results for reference compounds methotrexate, 1 and 2 as well as the N10-modified compound 4 in their neutral and N1-protonated variants and the PABA-modified compound 28 in neutral form as individual ligand:receptor complex PDB files. The files are ordered as ranked by Glide docking scores. The LmPTR1 receptor was based on PDB-ID 1e92 with explicit conserved structural water molecules. Docking results were obtained by Induced Fit docking with Schrödinger Glide
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PDB file of the prepared human dihydrofolate reductase docking receptor based on chain A of PDB-ID 1u72 with a conserved set of structural waters.

PDB file of the prepared human dihydrofolate reductase docking receptor based on chain A of PDB-ID 1u72 without additional water molecules.

PDB file of the prepared Leishmania major dihydrofolate reductase docking receptor based on a published homology model of LmDHFR (Panecka-Hofman et al. (2017) Biochim Biophys Acta Gen Subj. 1861(12), 3215-3230. DOI: 10.1016/j.bbagen.2017.09.012) without water molecules.

PDB file of the prepared Leishmania major pteridine reductase 1 docking receptor based on chain A of PDB-ID 1e92 with a conserved set of structural waters.

PDB file of the prepared Leishmania major pteridine reductase 1docking receptor based on chain A of PDB-ID 1e92 without additional water molecules.

PDB file of the prepared Trypanosoma brucei dihydrofolate reductase docking receptor based on chain A of PDB-ID 3rg9 without water molecules.

PDB file of the prepared Trypanosoma brucei pteridine reductase 1 docking receptor based on chain A of PDB-ID 2x9g with a conserved set of structural waters.

Structural models of the LAB PYKs of L. lactis, L. plantarum, S. pyogenes and E. faecalis including the "best" docking solutions of potential allosteric ligands. The structures were derived by homology modeling based on the template of E. coli and B. stearothermophilus.
PYK models and ligands are provided as .pdb files and can be displayed by using the program PyMOL, for instance.

This SOP describes the preparation of pteridine ligand 3D structures from SMILES or other input formats with the LigPrep routine as embedded in Schrödinger Maestro for usage in docking runs and in silico ADME-Tox property prediction.

This SOP describes the docking receptor preparation of PTR1 and DHFR receptor PDB files, performed with the Maestro Protein PrepWizard and the Glide grid generation routine. The optional identification and integration of conserved structural water molecules with the WatCH tool is also covered.

This SOP describes the in silico ADME-Tox property prediction with QikProp for prepared pteridine ligands.

This SOP describes the docking of pteridine libraries into PTR1 or DHFR target receptors, using Glide in Schrödinger Maestro with the XP (eXtra Precision) protocol.

This SOP describes the docking of pteridine libraries into PTR1 or DHFR target receptors, using Glide and Prime in Schrödinger Maestro as part of the Induced Fit workflow to allow for receptor side chain reorganization upon ligand binding.

Poster presented at the 12th International Conference on Systems Biology (ICSB), Heidelberg/Mannheim, August 28 - September 1, 2011.