FITTED (Software)

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Flexibility Induced Through Targeted Evolutionary Description
Developer(s)McGill University
Operating systemMicrosoft Windows Mac-OS

The program covers covalent docking, metalloprotein docking, docking to nucleic acids, and flexible protein side chains.[1][2] FITTED is the docking software of the Forecaster drug discovery platform.[3] Common applications of FITTED include large-scale virtual screening,[4] hit generation,[5] and lead optimization.[6]

Features and applications

FITTED is based on a Lamarckian genetic algorithm (GA) that uses a conjugate-gradient optimization method for local searches.[7] The GA accounts for the flexibility of the ligand and the macromolecule through crossover and mutations of side chain and backbone conformations, as well as the presence of bridging water molecules.

FITTED can dock ligands to metalloenzymes by using quantum mechanics (QM)-derived parameters and functions to describe the coordination geometry and atomic charge variability around the metal (Zinc, Iron, or Magnesium).[8][9] To describe the ligand-metal coordination process, a potential acid-base reaction between the ligand and a neighboring residue is considered when necessary.[8]

FITTED can dock ligands covalently.[9][5] The program automatically identifies and assigns the ligand covalent warhead atoms.[10] A covalent bond will be formed during docking only if the warhead is predicted to be in close proximity to the targeted residue. If no covalent docking binding pose is found to be energetically-favored, the ligand is docked non-covalently.[9]

Drug discovery

FITTED can be applied to find binders and inhibitors for a variety of targets.[11]

Including:

  • Covalent inhibitors targeting SARS-CoV-2 3CLpro[6]
  • Covalent and non-covalent inhibitors for prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP)[5][12][13][14]
  • Hepatitis C virus (HCV) polymerase inhibitors[15]
  • Histone deacetylase (HDAC) inhibitors[16]
  • G-quadruplex binders[17]

Accuracy

The latest reported accuracy of FITTED (June 2021)[9] is ~70% for self-docking (RMSD cutoff of 2.0Å) and ~50% for cross-docking (RMSD cutoff of 2.5Å) when the top 3 binding modes are considered. The accuracy for metalloprotein self-docking (magnesium and iron) is ~50%. When the top 10 binding modes are considered, FITTED identifies the correct binding mode in 90% of the cases.[9]

History and Use

In 2015, a study by Xu et al.[18] comparing 8 molecular docking programs and 16 different scoring functions for predicting the biological activities of ligands for protein targets found that FITTED, FlexX and GOLDScore outperformed the rest of the tested programs.

In 2018, a study by Scarpino et al.[10] evaluated six covalent docking programs and found that FITTED was capable of recovering 56% of experimental binding modes in the Top 1 predicted poses and 81% in the Top 10.

Supported operating systems

FITTED can be run on Windows, Linux, and MacOS, as part of the Forecaster drug discovery platform.[19] A Java-based graphical user interface (GUI) is provided for all operating systems.[9]

Licensing

FITTED is distributed as part of the Forecaster drug discovery platform by Molecular Forecaster Inc, company located in Montreal, Canada.[19] The Forecaster drug discovery platform is free for academia, while industrial users must purchase a license.[20]

References

  1. ↑ Moitessier, Nicolas; Pottel, Joshua; Therrien, Eric; Englebienne, Pablo; Liu, Zhaomin; Tomberg, Anna; Corbeil, Christopher R. (2016-09-20). "Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods". Accounts of Chemical Research. 49 (9): 1646–1657. doi:10.1021/acs.accounts.6b00185. ISSN 0001-4842.
  2. ↑ Moitessier, N; Englebienne, P; Lee, D; Lawandi, J; Corbeil, C R (March 2008). "Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go: Docking/scoring methods-a review". British Journal of Pharmacology. 153 (S1): S7–S26. doi:10.1038/sj.bjp.0707515. PMC 2268060. PMID 18037925.{{cite journal}}: CS1 maint: PMC format (link)
  3. ↑ Therrien, Eric; Englebienne, Pablo; Arrowsmith, Andrew G.; Mendoza-Sanchez, Rodrigo; Corbeil, Christopher R.; Weill, Nathanael; Campagna-Slater, Valérie; Moitessier, Nicolas (2012-01-23). "Integrating Medicinal Chemistry, Organic/Combinatorial Chemistry, and Computational Chemistry for the Discovery of Selective Estrogen Receptor Modulators with F orecaster , a Novel Platform for Drug Discovery". Journal of Chemical Information and Modeling. 52 (1): 210–224. doi:10.1021/ci2004779. ISSN 1549-9596. PMID 22133077.
  4. ↑ Burai-Patrascu, Mihai; Nivedha, Anita K.; Rostaing, Ophélie; Chukka, Prakash; Moitessier, Nicolas; Pottel, Josh (2022-08-02). "The First CACHE Challenge – Identifying Binders of the WD-Repeat Domain of Leucine-Rich Repeat Kinase 2". ChemRxiv. doi:10.26434/chemrxiv-2022-ncqsj.
  5. ↑ 5.0 5.1 5.2 De Cesco, Stéphane; Deslandes, Sébastien; Therrien, Eric; Levan, David; Cueto, Mickaël; Schmidt, Ralf; Cantin, Louis-David; Mittermaier, Anthony; Juillerat-Jeanneret, Lucienne; Moitessier, Nicolas (2012-07-17). "Virtual Screening and Computational Optimization for the Discovery of Covalent Prolyl Oligopeptidase Inhibitors with Activity in Human Cells". Journal of Medicinal Chemistry. 55 (14): 6306–6315. doi:10.1021/jm3002839. ISSN 0022-2623. PMID 22765237.
  6. ↑ 6.0 6.1 Stille, Julia K.; Tjutrins, Jevgenijs; Wang, Guanyu; Venegas, Felipe A.; Hennecker, Christopher; Rueda, Andrés M.; Sharon, Itai; Blaine, Nicole; Miron, Caitlin E.; Pinus, Sharon; Labarre, Anne; Plescia, Jessica; Burai Patrascu, Mihai; Zhang, Xiaocong; Wahba, Alexander S. (2022-02-05). "Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors". European Journal of Medicinal Chemistry. 229: 114046. doi:10.1016/j.ejmech.2021.114046. ISSN 0223-5234. PMC 8665847. PMID 34995923.
  7. ↑ Yuriev, Elizabeth; Agostino, Mark; Ramsland, Paul A. (2011). "Challenges and advances in computational docking: 2009 in review". Journal of Molecular Recognition: JMR. 24 (2): 149–164. doi:10.1002/jmr.1077. ISSN 1099-1352. PMID 21360606.
  8. ↑ 8.0 8.1 Pottel, Joshua; Therrien, Eric; Gleason, James L.; Moitessier, Nicolas (2014-01-27). "Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors". Journal of Chemical Information and Modeling. 54 (1): 254–265. doi:10.1021/ci400550m. ISSN 1549-9596. PMID 24364808.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Labarre, Anne; Stille, Julia K.; Patrascu, Mihai Burai; Martins, Andrew; Pottel, Joshua; Moitessier, Nicolas (2022-02-28). "Docking Ligands into Flexible and Solvated Macromolecules. 8. Forming New Bonds─Challenges and Opportunities". Journal of Chemical Information and Modeling. 62 (4): 1061–1077. doi:10.1021/acs.jcim.1c00701. ISSN 1549-9596. PMID 35133156.
  10. ↑ 10.0 10.1 Scarpino, Andrea; Ferenczy, György G.; Keserű, György M. (2018-07-23). "Comparative Evaluation of Covalent Docking Tools". Journal of Chemical Information and Modeling. 58 (7): 1441–1458. doi:10.1021/acs.jcim.8b00228. ISSN 1549-9596. PMID 29890081.
  11. ↑ Moitessier, Nicolas; Pottel, Joshua; Therrien, Eric; Englebienne, Pablo; Liu, Zhaomin; Tomberg, Anna; Corbeil, Christopher R. (2016-09-20). "Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods". Accounts of Chemical Research. 49 (9): 1646–1657. doi:10.1021/acs.accounts.6b00185. ISSN 0001-4842. PMID 27529781.
  12. ↑ Plescia, Jessica; Hédou, Damien; Pousse, Maud Eva; Labarre, Anne; Dufresne, Caroline; Mittermaier, Anthony; Moitessier, Nicolas (2022-10-05). "Modulating the selectivity of inhibitors for prolyl oligopeptidase inhibitors and fibroblast activation protein-α for different indications". European Journal of Medicinal Chemistry. 240: 114543. doi:10.1016/j.ejmech.2022.114543. ISSN 0223-5234. PMID 35797897.
  13. ↑ Plescia, Jessica; Dufresne, Caroline; Janmamode, Naëla; Wahba, Alexander S.; Mittermaier, Anthony K.; Moitessier, Nicolas (2020-01-01). "Discovery of covalent prolyl oligopeptidase boronic ester inhibitors". European Journal of Medicinal Chemistry. 185: 111783. doi:10.1016/j.ejmech.2019.111783. ISSN 0223-5234. PMID 31732257.
  14. ↑ Mariaule, Gaëlle; De Cesco, Stéphane; Airaghi, Francesco; Kurian, Jerry; Schiavini, Paolo; Rocheleau, Sylvain; Huskić, Igor; Auclair, Karine; Mittermaier, Anthony; Moitessier, Nicolas (2016-05-12). "3-Oxo-hexahydro-1 H -isoindole-4-carboxylic Acid as a Drug Chiral Bicyclic Scaffold: Structure-Based Design and Preparation of Conformationally Constrained Covalent and Noncovalent Prolyl Oligopeptidase Inhibitors". Journal of Medicinal Chemistry. 59 (9): 4221–4234. doi:10.1021/acs.jmedchem.5b01296. ISSN 0022-2623. PMID 26619267.
  15. ↑ Corbeil, Christopher R.; Englebienne, Pablo; Yannopoulos, Constantin G.; Chan, Laval; Das, Sanjoy K.; Bilimoria, Darius; L’Heureux, Lucille; Moitessier, Nicolas (2008-04-01). "Docking Ligands into Flexible and Solvated Macromolecules. 2. Development and Application of F itted 1.5 to the Virtual Screening of Potential HCV Polymerase Inhibitors". Journal of Chemical Information and Modeling. 48 (4): 902–909. doi:10.1021/ci700398h. ISSN 1549-9596. PMID 18341269.
  16. ↑ Mendoza-Sanchez, Rodrigo; Cotnoir-White, David; Kulpa, Justyna; Jutras, Isabel; Pottel, Joshua; Moitessier, Nicolas; Mader, Sylvie; Gleason, James L. (2015-12-15). "Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids". Bioorganic & Medicinal Chemistry. 23 (24): 7597–7606. doi:10.1016/j.bmc.2015.11.005. ISSN 0968-0896. PMID 26613635.
  17. ↑ Castor, Katherine J.; Liu, Zhaomin; Fakhoury, Johans; Hancock, Mark A.; Mittermaier, Anthony; Moitessier, Nicolas; Sleiman, Hanadi F. (2013-12-23). "A Platinum(II) Phenylphenanthroimidazole with an Extended Side-Chain Exhibits Slow Dissociation from a c-Kit G-Quadruplex Motif". Chemistry - A European Journal. 19 (52): 17836–17845. doi:10.1002/chem.201301590. PMID 24249701.
  18. ↑ Xu, Weijun; Lucke, Andrew J.; Fairlie, David P. (2015-04-01). "Comparing sixteen scoring functions for predicting biological activities of ligands for protein targets". Journal of Molecular Graphics and Modelling. 57: 76–88. doi:10.1016/j.jmgm.2015.01.009. ISSN 1093-3263. PMID 25682361.
  19. ↑ 19.0 19.1 "- Molecular Forecaster Inc. Download". Molecular Forecaster Inc. Retrieved 2022-12-01.
  20. ↑ "Licenses". Molecular Forecaster Inc. Retrieved 2022-12-01.

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