High-throughput docking + reevaluation of top hits & docked poses

to be disclosed later

The hit identification and drug discovery strategy consistes in high-throughput docking for the identification of quality, developable LRRK2 modulators. Several large libraries of commercially available compounds (VitasM, LifeChemicals, MolPort, Enamine) were downloaded and prepared using the LigPrep preparation workflow from Maestro (Schrödinger, Inc). Briefly, the main tautomers from each compound were generated and only compounds with reasonable physico-chemical properties were considered (e.g., molecular weight, HBAcc/HBDon, number of rings, log P/D, PSA, ligand flexibility, as well as number of chiral centers. We used our proprietary OICR HTS Filters to eliminate reactive and chemically unstable compounds, compounds with undesorable functional groups, e.g., number of nitro and cyano groups, linear urea and amides, number of halogen atoms, hydrogen peroxide inducers, and Pan-Assay INterfeering Structures (PAINS). The virtual screening stage consisted in a two-step molecular docking workflow using the popular Glide (Schrödinger, Inc) docking tool. The simulations were performed on both chains from the 6DLO PDB structure. All the compounds were docked using the SP function. Then, the top 10K compounds from each database were docked using the more accurate XP function. Top 2K poses from both SP and XP scoring functions, from each virtual screening simulation, were finally merged before the refinement stage. The extracted poses were subsequently reevaluated using the independent SeeSAR (BioSolveIT) tool using the HYDE scoring function that places and takes into account structural waters, ligand conformational strain and unfavorable desolvation effects. This structure-based software was mainly used to discard putative false positives from virtual screening (e.g., poses with either geometry or energy warnings). Finally, a thorough visual inspection by experienced computational and medicinal chemists over all kept poses was then conducted to select the most promising compounds to be experimentally tested.

High-throughput docking, with rescoring using structural waters and ligand conformational strain

Glide/Maestro/Drug Discovery suite (Schrödinger, Inc), SeeSAR (BioSolveIT), BIOVIA Pipeline Pilot.

N/A

1. OICR-Janssen deal (the project initiated based on VS of eMolecules database): https://www.pharmaceutical-business-review.com/news/oicr-novera-and-janssen-biotech-collaborate-to-develop-haematological-cancer-drug-151015-4693923/ 2. OICR-Celgene deal (major breakthough of the project wqs based on a focused virtual library design, followed up with docking of tens of thousand analogs): https://oicr.on.ca/first-in-class-drug-for-blood-cancers-discovered-by-ontario-researchers-receives-record-setting-industry-investment%EF%BB%BF/ 3. Hoffer L. et al. "Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach." J. Med. Chem. 2018 Jul 12;61(13):5719-5732 4. Hoffer L. et al. "CovaDOTS: In Silico Chemistry-Driven Tool to Design Covalent Inhibitors Using a Linking Strategy." J. Chem. Inf. Model. 2019 Apr 22;59(4):1472-1485 5. Ariey-Bonnet J. et al. "In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor." Mol Oncol. 2020 Dec;14(12):3083-3099 6. Getlik, Matthäus; et al. “Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).” J. Med. Chem. 2016, 59(6), 2478-2496 7. Grebien, Florian; Vedadi, Masoud; Getlik, Matthaeus; Giambruno, Roberto; Grover, Amit; Avellino, Roberto; Vittori, Sarah; Kuznetsova, Ekaterina; Smil, David; Barsyte-Loverjoy, Dalia; Li, Fengling; Poda, Gennadiy; Schapira, Matthieu; Wu, Hong; Dong, Aiping; Senistera, Guillermo; Schonegger, Andreas; Bilban, Martin; Bock, Christopher; Brown, Peter J.; Zuber, Johannes; Bennett, Keiryn; Al-awar, Rima; Delwel, Ruud; Nerlov, Claus; Arrowsmith, Cheryl H.; Superti-Furga, Giulio. “C/EBPa N-Terminal Leukemia is Sensitive to Pharmacological Targeting of the WDR5-MLL Interaction.” Nature Chem. Biol. 2015, 11(8), 571-578 8. Poda, Gennady; Tanchuk, Vsevolod. “Computational Methods for the Discovery of Chemical Probes.” In: RSC Book Series “Discovery and Utility of Chemical Probes in Target Discovery”, Ed. Paul Brennan, December 2020, Oxford Press 9. Al-awar, Rima; Isaac, Methvin; Chau, Anh M.; Mamai, Ahmed; Watson, Iain; Poda, Gennady; Subramanian, Pandiaraju; Wilson, Brian; Uehling, David “Tricyclic Inhibitors of the BCL6 BTB Domain Protein-Protein Interaction and Uses Thereof” (Ontario Institute for Cancer Research). US Patent App. 16/955,975, 2021 10. Al-awar, Rima; Isaac, Methvin; Chau, Anh M.; Mamai, Ahmed; Watson, Iain; Poda, Gennady; Subramanian, Pandiaraju; Wilson, Brian; Uehling, David; Prakesch, Michael; Babu, Joseph; Morin, Justin-Alexander “Inhibitors of the BCL6 BTB Domain Protein-Protein Interaction and Uses Thereof” (Ontario Institute for Cancer Research). US Patent App. 16/690,924, 2020 11. Al-awar, Rima; Isaac, Methvin; Joseph, Babu; Liu, Yong; Mamai, Ahmed; Poda, Gennady; Subramanian, Pandiaraju; Uehling, David; Wilson, Brian; Zepeda-Velazquez, Carlos “Inhibitors of WDR5 protein-protein binding” (Ontario Institute for Cancer Research), US Patent App. 16/643,633, 2020 12. Al-awar, Rima; Zepeda-Velazquez, Carlos; Poda, Gennady; Isaac, Methvin; Uehling, David; Wilson, Brian; Joseph, Babu; Liu, Yong; Subramanian, Pandiaraju; Mamai, Ahmed; Prakesch, Michael; Stille, Julia K. “Inhibitors of WDR5 protein-protein binding” (Ontario Institute for Cancer Research), US Patent App. 16/080,866, 2019. 13. Al-awar, Rima; Zepeda-Velazquez, Carlos; Poda, Gennady; Isaac, Methvin; Uehling, David; Wilson, Brian; Joseph, Babu; Liu, Yong; Subramanian, Pandiaraju; Mamai, Ahmed “Inhibitors of WDR5 protein-protein binding” (Ontario Institute for Cancer Research), US Patent App. 16/080,851, 2019 14. Al-awar, Rima; Isaac, Methvin; Chau, Anh M.; Mamai, Ahmed; Watson, Iain; Poda, Gennady; Subramanian, Pandiaraju; Wilson, Brian; Uehling, David “Tricyclic Inhibitors of the BCL6 BTB Domain Protein-Protein Interaction and Uses Thereof” (Ontario Institute for Cancer Research). WO/2019/119145, PCT/CA2018/051643, Priority to US 62/608,869, 2017 15. Al-awar, Rima; Zepeda-Velazquez, Carlos; Poda, Gennady; Isaac, Methvin; Uehling, David; Wilson, Brian; Joseph, Babu; Liu, Yong; Subramanian, Pandiaraju; Mamai, Ahmed; Prakesch, Michael; Stille, Julia K. “Inhibitors of WDR5 protein-protein binding” (Ontario Institute for Cancer Research). WO/2017/147700, PCT/CA2017/050269, Priority to US 201662/301,673, 2017 16. Al-awar, Rima; Zepeda, Carlos; Poda, Gennady; Isaac, Methvin; Uehling, David; Wilson, Brian; Joseph, Babu; Liu, Yong; Subramanian, Pandiaraju; Mamai, Ahmed; Prakesch, Michael; Stille, Julia K. “Inhibitors of WDR5 protein-protein binding” (OICR). WO/2017/147701, PCT/CA2017/050271, Priority to US 201662/301,678, 2017.

Focused virtual library design, high-throughput docking, reevaluation of top hits & docked poses

to be disclosed later.

Pretty much what was described above, plus we will use focused virtual library design and our machine learning and in silico ADMET models.

Focused library design, high-throughput docking, with rescoring using structural waters and ligand conformational strain, machine learning and in silico ADMET models.

Glide/Maestro/Drug Discovery suite (Schrödinger, Inc), SeeSAR (BioSolveIT), BIOVIA Pipeline Pilot.

N/A

Please see above.