Software:Fitted

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Short description: Molecular docking program - FITTED


FITTED (Flexibility Induced Through Targeted Evolutionary Description) is a molecular docking program developed at McGill University by the Moitessier Research Group.[1] The program covers covalent docking, metalloprotein docking, docking to nucleic acids, and flexible protein side chains.[2][3][4][5][6][7][8][9] FITTED is the docking software of the Forecaster drug discovery platform.[10] Common applications of FITTED include large-scale virtual screening,[11] hit generation,[12] and lead optimization.[13]

Features and applications

FITTED is based on a Lamarckian genetic algorithm (GA) that uses a conjugate-gradient optimization method for local searches.[1][14] The GA accounts for the flexibility of the ligand and the macromolecule through crossover and mutations of multiple side chain and backbone conformations, as well as the presence of bridging water molecules.[1]

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).[6][8] To describe the ligand-metal coordination process, a potential acid-base reaction between the ligand and a neighboring residue is considered when necessary.[6]

FITTED can dock ligands covalently.[8][12] The program automatically identifies and assigns the ligand covalent warhead atoms.[15] 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.[8]

Accuracy

The latest reported accuracy of FITTED (June 2021)[8] 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.[8]

Applications in drug discovery

FITTED has been applied to find binders and inhibitors for a variety of targets.[16] Study cases include:

Comparative studies

Two independent comparative studies have included FITTED in the list of tested programs.

In 2015, a study by Xu et al.[21] 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.[15] 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.[22] A Java-based graphics user interface (GUI) is provided for all operating systems.[8]

Licensing

FITTED is distributed as part of the Forecaster drug discovery platform by Molecular Forecaster Inc., a research-as-a-service (RaaS) company located in Montreal, Canada.[22] The Forecaster drug discovery platform is free for academia, while industrial users must purchase a license.[23]

References

  1. ↑ 1.0 1.1 1.2 Corbeil, Christopher R.; Englebienne, Pablo; Moitessier, Nicolas (2007-03-01). "Docking Ligands into Flexible and Solvated Macromolecules. 1. Development and Validation of FITTED 1.0" (in en). Journal of Chemical Information and Modeling 47 (2): 435–449. doi:10.1021/ci6002637. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci6002637. 
  2. ↑ 2.0 2.1 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" (in en). Journal of Chemical Information and Modeling 48 (4): 902–909. doi:10.1021/ci700398h. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci700398h. 
  3. ↑ Corbeil, Christopher R.; Moitessier, Nicolas (2009-04-27). "Docking Ligands into Flexible and Solvated Macromolecules. 3. Impact of Input Ligand Conformation, Protein Flexibility, and Water Molecules on the Accuracy of Docking Programs" (in en). Journal of Chemical Information and Modeling 49 (4): 997–1009. doi:10.1021/ci8004176. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci8004176. 
  4. ↑ Englebienne, Pablo; Moitessier, Nicolas (2009-06-22). "Docking Ligands into Flexible and Solvated Macromolecules. 4. Are Popular Scoring Functions Accurate for this Class of Proteins?" (in en). Journal of Chemical Information and Modeling 49 (6): 1568–1580. doi:10.1021/ci8004308. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci8004308. 
  5. ↑ Englebienne, Pablo; Moitessier, Nicolas (2009-11-23). "Docking Ligands into Flexible and Solvated Macromolecules. 5. Force-Field-Based Prediction of Binding Affinities of Ligands to Proteins" (in en). Journal of Chemical Information and Modeling 49 (11): 2564–2571. doi:10.1021/ci900251k. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci900251k. 
  6. ↑ 6.0 6.1 6.2 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" (in en). Journal of Chemical Information and Modeling 54 (1): 254–265. doi:10.1021/ci400550m. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci400550m. 
  7. ↑ Therrien, Eric; Weill, Nathanael; Tomberg, Anna; Corbeil, Christopher R.; Lee, Devin; Moitessier, Nicolas (2014-11-24). "Docking Ligands into Flexible and Solvated Macromolecules. 7. Impact of Protein Flexibility and Water Molecules on Docking-Based Virtual Screening Accuracy" (in en). Journal of Chemical Information and Modeling 54 (11): 3198–3210. doi:10.1021/ci500299h. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci500299h. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 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" (in en). Journal of Chemical Information and Modeling 62 (4): 1061–1077. doi:10.1021/acs.jcim.1c00701. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/acs.jcim.1c00701. 
  9. ↑ 9.0 9.1 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" (in en). Chemistry - A European Journal 19 (52): 17836–17845. doi:10.1002/chem.201301590. https://onlinelibrary.wiley.com/doi/10.1002/chem.201301590. 
  10. ↑ 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" (in en). Journal of Chemical Information and Modeling 52 (1): 210–224. doi:10.1021/ci2004779. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/ci2004779. 
  11. ↑ 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" (in en). ChemRxiv. doi:10.26434/chemrxiv-2022-ncqsj. https://chemrxiv.org/engage/chemrxiv/article-details/62e7eb52adfd35021f23362c. 
  12. ↑ 12.0 12.1 12.2 De Cesco, Stéphane; Deslandes, Sébastien; Therrien, Eric; Levan, David; Cueto, Mickaël; Schmidt, Ralf; Cantin, Louis-David; Mittermaier, Anthony et al. (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. http://dx.doi.org/10.1021/jm3002839. 
  13. ↑ 13.0 13.1 Stille, Julia K.; Tjutrins, Jevgenijs; Wang, Guanyu; Venegas, Felipe A.; Hennecker, Christopher; Rueda, Andrés M.; Sharon, Itai; Blaine, Nicole et al. (2022-02-05). "Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors" (in en). European Journal of Medicinal Chemistry 229: 114046. doi:10.1016/j.ejmech.2021.114046. ISSN 0223-5234. https://www.sciencedirect.com/science/article/pii/S0223523421008953. 
  14. ↑ 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. https://pubmed.ncbi.nlm.nih.gov/21360606/. 
  15. ↑ 15.0 15.1 Scarpino, Andrea; Ferenczy, György G.; Keserű, György M. (2018-07-23). "Comparative Evaluation of Covalent Docking Tools" (in en). Journal of Chemical Information and Modeling 58 (7): 1441–1458. doi:10.1021/acs.jcim.8b00228. ISSN 1549-9596. https://pubs.acs.org/doi/10.1021/acs.jcim.8b00228. 
  16. ↑ 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" (in en). Accounts of Chemical Research 49 (9): 1646–1657. doi:10.1021/acs.accounts.6b00185. ISSN 0001-4842. https://pubs.acs.org/doi/10.1021/acs.accounts.6b00185. 
  17. ↑ 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" (in en). European Journal of Medicinal Chemistry 240: 114543. doi:10.1016/j.ejmech.2022.114543. ISSN 0223-5234. https://www.sciencedirect.com/science/article/pii/S0223523422004457. 
  18. ↑ 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" (in en). European Journal of Medicinal Chemistry 185: 111783. doi:10.1016/j.ejmech.2019.111783. ISSN 0223-5234. https://www.sciencedirect.com/science/article/pii/S0223523419309353. 
  19. ↑ Mariaule, Gaëlle; De Cesco, Stéphane; Airaghi, Francesco; Kurian, Jerry; Schiavini, Paolo; Rocheleau, Sylvain; Huskić, Igor; Auclair, Karine et al. (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" (in en). Journal of Medicinal Chemistry 59 (9): 4221–4234. doi:10.1021/acs.jmedchem.5b01296. ISSN 0022-2623. https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01296. 
  20. ↑ 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" (in en). Bioorganic & Medicinal Chemistry 23 (24): 7597–7606. doi:10.1016/j.bmc.2015.11.005. ISSN 0968-0896. https://www.sciencedirect.com/science/article/pii/S0968089615301309. 
  21. ↑ Xu, Weijun; Lucke, Andrew J.; Fairlie, David P. (2015-04-01). "Comparing sixteen scoring functions for predicting biological activities of ligands for protein targets" (in en). Journal of Molecular Graphics and Modelling 57: 76–88. doi:10.1016/j.jmgm.2015.01.009. ISSN 1093-3263. https://www.sciencedirect.com/science/article/pii/S1093326315000285. 
  22. ↑ 22.0 22.1 "- Molecular Forecaster Inc. Download" (in en-US). https://molecularforecaster.com/download/. 
  23. ↑ "Licenses" (in en-US). https://molecularforecaster.com/licenses/. 



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