Pteridines as anti-kinetoplastid folate-pathway protein inhibitors

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

DOI: 10.15490/fairdomhub.1.investigation.417.1

Zenodo URL: None

Created at: 8th Jun 2022 at 10:08

Contents

In silico property and correlation analysis

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.

In silico ADMET data prediction

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

QikProp data for reference pteridines and N10-, PABA- and tail-modified series compounds

Results of default run of Schrödinger QikProp (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, QikProp v4.6.) for reference pteridines (series 1) and newly synthesized N10-, PABA and tail-modified pteridines (series 2, 3 and 4). QikProp in silico predicts various physico-chemical compound properties and advanced descriptors related to administration, distribution, metabolism, excretion and toxicity of the compounds.

  • qikprop-results_reference-new-pteridines.csv

QikProp data for merged series compounds (series 5)

Results of default run of Schrödinger QikProp (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, QikProp v4.6.) for newly synthesized compounds of the merged series (5a-5f). QikProp in silico predicts various physico-chemical compound properties and advanced descriptors related to administration, distribution, metabolism, excretion and toxicity of the compounds.

  • qikprop-results_mergedseries.csv

QikProp data for pteridine in silico library

Results of default run of Schrödinger QikProp (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, QikProp v4.6.) for the entire in silico pteridine library. QikProp in silico predicts various physico-chemical compound properties and advanced descriptors related to administration, distribution, metabolism, excretion and toxicity of the compounds.

  • qikprop-results_insilicolibrary-pteridines.csv

ADMET-property prediction SOP with QikProp

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

  • sop_qikprop-run.pdf

Correlation analysis between predicted ADMET properties and anti-parasitic activity

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.

Python module for calculating pairwise correlation coefficients for Qikprop descriptors and measured activity data

Zip file with Python module used to correlate compound descriptors predicted with Schroedinger QikProp with observed anti-parasitic effect against T. brucei brucei bloodstream forms. The script allows a leave-one-out analysis in addition to the default correlation analysis, where data for each compound is skipped once before the correlation analysis is re-performed. An example config file is provided with the zip-archive. For further instructions and information on the available settings, also
...

  • propertyActivityCorrelations.zip

Correlation analysis between PTR1 and DHFR activities and anti-parasitic activity

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.

Python module for calculating trivariate statistics between three activities

Zip-file with Python module used to calculate trivariate statistics between the inhibition of parasitic target enzymes pteridine reductase 1 and dihydrofolate reductase and the corresponding inhibition of T. brucei brucei bloodstream forms. The script makes use of an expansion of pairwise Pearson or Spearman correlations. For further details, also refer to the README file.

  • trivariateStats.zip

PAINS filtering

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

FAF-Drugs4 PAINS filtering results and additional ADMET data

Pteridines checked for Pan-assay interference compounds with the FAF-Drugs4 webserver (https://fafdrugs4.rpbs.univ-paris-diderot.fr/, last checked August 2020 and Lagorce et al. (2015) Nucleic Acids Res. 43, W200–207). Archive of PAINS filtering and ADME-Tox prediction results from FAF-Drugs4 run performed April 2019 with compound SMILES as input: applied_filters.txt: list of filters used; compound.sdf, accepted.sdf, intermediate.sdf, rejected.sdf, covalent_inhibitors.sdf and pains.sdf: compound
...

  • faf4drugs_painsFilter.zip

Docking to PTR1 and DHFR targets and off-targets

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.

Compound library preparation

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

SMILES strings for resynthesized and newly designed pteridine compounds

Compound SMILES of resynthesized or newly designed pteridine compounds 1b, 1c, 2a-e, 3a-e, 4a-j and 5a-f used for ligand preparation within Maestro (Schrödinger, LLC, New York, NY, Schrödinger Release 2015-4, 2015, Maestro.). SMILES strings and compound identifiers are comma-separated and can be readily imported in Maestro.

  • pteridines_smiles.smi

SDF files of protonated pteridine compounds

Zip archive of N1 protonated reference and newly synthesized pteridines (series 1-5) in SDF format.

  • protonated-sdf.zip

Fragments used for construction of the in silico pteridine library

Summary of fragments that were used to construct an in silico pteridine library with corresponding fragment identifiers. Connections between the fragments are shown outside the colored boxes. Compounds were composed of a core fragment (C1-C3), an N10 fragment (N1-N7), a PABA fragment (P1-P10) and, for any PABA fragment except P8, P9 and P10, a tail fragment (T1E1-T7).

  • insilico_library_fragments.pdf

Ligand 3D structure preparation SOP

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.

  • sop_ligandpreparation.pdf

Docking receptor preparation

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.

hDHFR docking receptor with conserved structural water

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.

  • hDHFR-cW_docking-receptor.pdb

hDHFR docking receptor without water

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

  • hDHFR-no_docking-receptor.pdb

LmDHFR docking receptor without 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.

  • LmDHFR-no_docking-receptor.pdb

LmPTR1 docking receptor with conserved structural water

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.

  • LmPTR1-cW_docking-receptor.pdb

LmPTR1 docking receptor without water molecules

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

  • LmPTR1-no_docking-receptor.pdb

TbDHFR docking receptor without water molecules

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

  • TbDHFR-no_docking-receptor.pdb

TbPTR1 docking receptor with conserved structural water

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.

  • TbPTR1-cW_docking-receptor.pdb

TbPTR1 docking receptor without water molecules

PDB file of the prepared Trypanosoma brucei pteridine reductase 1 docking receptor based on chain A of PDB-ID 2x9g without additional water molecules.

  • TbPTR1-no_docking-receptor.pdb

Protein receptor preparation SOP for docking

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.

  • sop_receptorpreparation.pdf

Rigid-body docking studies

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.

PDB files of pteridine docking results in hDHFR with explicit conserved structural water molecules

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 hDHFR receptor based on PDB-ID 1u72 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.
...

  • hDHFR-cW.zip

PDB files of pteridine docking results in hDHFR without explicit water molecules

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 hDHFR receptor based on PDB-ID 1u72 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.

  • hDHFR-noHOH.zip

PDB files of pteridine docking results in LmDHFR without explicit water molecules

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 LmDHFR receptor based on the 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 explicit water molecules. Docking results obtained by rigid-body XP docking with Schrödinger Glide (Schrödinger, LLC, New York,
...

  • LmDHFR.zip

PDB files of pteridine docking results in LmPTR1 with explicit conserved structural water molecules

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.
...

  • LmPTR1-cW.zip

PDB files of pteridine docking results in LmPTR1 without explicit water molecules

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.

  • LmPTR1-noHOH.zip

PDB files of pteridine docking results in TbDHFR without explicit water molecules

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.

  • TbDHFR.zip

PDB files of pteridine docking results in TbPTR1 with explicit conserved structural water molecules

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.
...

  • TbPTR1-cW.zip

PDB files of pteridine docking results in TbPTR1 without explicit water molecules.

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.

  • TbPTR1-noHOH.zip

Rigid-body XP docking with Glide

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.

  • sop_glide-xp-docking.pdf

Induced-fit docking studies

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.

PDB files of induced fit docking results for the reference pteridine MTX in hDHFR with explicit conserved structural water molecules

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
...

  • hDHFR-cW.zip

PDB files of induced fit docking results for the reference pteridine MTX in hDHFR without water molecules

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
...

  • hDHFR-noHOH.zip

PDB files of induced fit docking results for the reference pteridine MTX in LmDHFR without water molecules

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
...

  • LmDHFR.zip

PDB files of induced fit docking results for the reference pteridine MTX in TbDHFR without water molecules

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
...

  • TbDHFR.zip

PDB files of induced fit docking results for selected reference, N10- and PABA-modified pteridines in LmPTR1 with explicit conserved structural water molecules

Zip-archive with induced fit docking results for reference compounds methotrexate, 1b and 1c as well as the N10-modified compound 2e in their neutral and N1-protonated variants and the PABA-modified compound 3e 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
...

  • LmPTR1-cW.zip

PDB files of induced fit docking results for selected reference, N10- and Tail-modified pteridines in LmPTR1 without water molecules

Zip-archive with induced fit docking results for reference compounds methotrexate, 1b and 1c as well as the N10-modified compound 2e in their neutral and N1-protonated variants and the N10-modified compound 2a and Tail-modified compounds 4e, 4f, 4i and 4j 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
...

  • LmPTR1-noHOH.zip

PDB files of induced fit docking results for selected reference, N10- and merged-series pteridines in TbPTR1 with explicit conserved structural water molecules

Zip-archive with induced fit docking results for reference compounds methotrexate and 1b as well as the N10-modified compounds 2a and 2e in their neutral and N1-protonated variants and the N10-modified compound 2c and merged-series compound 5e 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
...

  • TbPTR1-cW.zip

PDB files of induced fit docking results for selected reference, N10- and PABA-modified pteridines in TbPTR1 without water molecules

Zip-archive with induced fit docking results for reference compounds methotrexate and 1b as well as the N10-modified compounds 2a and 2e in their neutral and N1-protonated variants and the PABA-modified compound 3d 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
...

  • TbPTR1-noHOH.zip

Induced fit docking with Glide and Prime as part of the Induced Fit docking workflow

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.

  • sop_induced-fit-docking.pdf
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Citation
Poehner, I., Wade, R., Panecka-Hofman, J., & Cordeiro-Da-Silva, A. (2022). Pteridines as anti-kinetoplastid folate-pathway protein inhibitors. FAIRDOMHub. https://doi.org/10.15490/FAIRDOMHUB.1.INVESTIGATION.417.1
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Created: 8th Jun 2022 at 10:08

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