Drug development for neglected parasitic diseases

The New Medicines for Trypanosomatidic Infections - NMTrypI project aimed at obtaining new candidate drugs against Trypanosomatidic infections with appropriate efficiency from the lead phase to the final preclinical phase that are more accessible to patients.

Design, synthesis, computational studies and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

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

Induced fit docking studies of the dinitroaniline parent trifluraline and the newly designed dinitroaniline-etherphospholipid hybrids against different potential binding sites in monomeric and multimeric kinetoplastid tubulin receptors.

Sequence and electrostatic potential analyses to identify sites in tubulins that differ between dinitroaniline-sensitive and dinitroaniline-resistant species.

Chemical structures, physicochemical properties and biological results for the compounds of the Ty-Box library

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.

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.

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.

Compound data and computational prediction of physicochemical properties

Prepared multimeric tubulin protein receptors for docking studies, generated by alignment of two identical models of alpha-tubulin on alpha-tubulin chains of two neighboring protofilaments.

Docking results of trifluraline and dinitroaniline-etherphospholipid hybrids against different kinetoplastid alpha-tubulin receptors with an induced fit docking routine. The docking protocol involves an initial crude ligand placement step, subsequent receptor optimization in response to ligand binding, and another docking step into the optimized receptor.

Alignments of various alpha-tubulin and beta-tubulin sequences from dinitroaniline-sensitive and dinitroaniline-resistant species. Sequences were retrieved from UniProt with the identifiers listed below and subjected to a multiple sequence alignment using ClustalOmega (ebi.ac.uk/Tools/msa/clustalo/; ClustalOmega webserver, last accessed 16-02-23):

alpha-tubulin:

• [dinitroaniline sensitive] T. cruzi - Q27352; T. brucei brucei - Q4GYY5; L. infantum - ...

Creation of homology models of various tubulins from dinitroaniline-sensitive and -resistant species, and a comparative analysis of their electrostatic potential grids overall and in putative binding site regions using PIPSA (Protein Interaction Property Similarity Analysis).

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the resulting complex of reference compound trifluralin to the N-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for dinitroaniline etherphospholipid hybrid compounds 1-4 and 7-8 docked to the resulting complex of reference compound trifluralin in the pironetin site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering). No results were obtained for compounds 5, 6 and 9.

The docking results were obtained by Induced Fit docking with ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1, 4, 8 and reference compound trifluraline, docked to the Consensus site (Delye, Mitra & Sept) of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Thr239 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1, 2, 4, 8 and reference compound trifluraline, docked to the pironetin site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Leu238 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow (Schrödinger, LLC, ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1-2, 4-5 and 7-8, docked to the resulting complex of reference compound trifluralin in the Blume site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering). No results were obtained for compounds 3, 6 and 9.

The docking results were obtained by Induced Fit docking ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1-5 and 7-8, docked to the resulting complex of reference compound trifluralin in the Consensus site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering). No results were obtained for compounds 6 and 9.

The docking results were obtained by Induced Fit docking ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the resulting complex of reference compound trifluralin to the M-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the interface region between two neighboring alpha-tubulin monomers of Trypanosoma brucei; alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilamentsof the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region residue ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, and reference compound trifluraline, docked to the M-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the M-loop region residue Leu286 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, and reference compound trifluralin, docked to the N-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the N-loop region residue Phe49 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the interface region between two neighboring alpha-tubulin monomers of Trypanosoma cruzi; alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilaments of the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region residue ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for dinitroaniline etherphospholipid hybrid compounds 1, 2, 4, 5 and 9 and reference compound trifluraline, docked to the Blume site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Ala4 (T. cruzi numbering). No results were obtained with compounds 3 and 6-8.

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1, 4, 8 and reference compound trifluraline, docked to the Consensus site (Delye, Mitra & Sept) of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Thr239 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the M-loop region of a Leishmania infantum alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the M-loop region residue Leu286 (T. cruzi numbering).

The 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 ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the N-loop region of a Leishmania infantum alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the N-loop region residue Phe49 (T. cruzi numbering).

The 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 ...

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the interface region between two neighboring alpha-tubulin monomers of Leishmania infantum; alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilaments of the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region ...

SOP describing application of the Induced fit docking workflow to Trypanosoma and Leishmania alpha-tubulin receptors.

General SOP for the webPIPSA workflow to study electrostatic potential differences of full alpha-tubulin homology models and various putative binding site regions

General SOP for alpha-tubulin homology model building

SOP for protein preparation steps performed for alpha-tubulin homology models (hydrogen addition, hydrogen bonding network optimization and energy minimization)

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.