Integrating Medicinal Chemistry         and Computational Chemistry:       The Molecular Forecaster Approach              ...
Company Profile• Founded in 2010 by Dr. Eric Therrien and Prof. Nicolas  Moitessier• Large work experience in medicinal, s...
Our Expertise• Virtual High-throughput screen of commercial or corporate libraries  of small molecules (vHTS)• In silico l...
The Molecular Forecaster Approach• Accurate software  – Software/methods combine advanced physics,    biochemistry and che...
Service Contracts• Secure  – High level of protection and confidentiality for you data  – MFI Never retain any IP on the m...
Our in-house Software• FITTED docking program    • Flexible protein    • Displaceable water molecules    • Automated coval...
The Forecaster Platform                      J. Chem Inf. Model. 2012, 52, 210
Virtual Screening of Covalent POP Inhibitors•   Prolyl OligoPeptidase involved in neurogenerative diseases (e.g. Alzheimer...
Virtual Screening of HCV Polymerase Inhibitors• Challenging enzyme for docking methods• Validation experiments carried out...
Binding to G-quadruplex• A platinum supramolecular square as an effective G-quadruplex binder  and telomerase inhibitor• M...
Platinum(II) Phenanthroimidazoles for TargetingTelomeric G-Quadruplexes                   • Experimental analyses and mole...
Discovery of Vitamin D ReceptorAntagonists• Modeling studies indicate that antagonism arises from side chain rigidity,  wh...
Retinoic Acid Receptors                • FITTED was first tested for its ability to                  extract actives molec...
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Molecular Forecaster Services

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Services offered at Molecular Forecaster Inc. and recent representative work.

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Molecular Forecaster Services

  1. 1. Integrating Medicinal Chemistry and Computational Chemistry: The Molecular Forecaster Approach Molecular Forecaster Inc.www.molecularforecaster.com
  2. 2. Company Profile• Founded in 2010 by Dr. Eric Therrien and Prof. Nicolas Moitessier• Large work experience in medicinal, synthetic and computational chemistry in both academic and industrial environments• Experimentalists with expertise in molecular modeling• We use our “chemical intuition” to solve problems• We developed our own programs with unique features
  3. 3. Our Expertise• Virtual High-throughput screen of commercial or corporate libraries of small molecules (vHTS)• In silico lead optimization (structure- and ligand-based)• Virtual combinatorial library design• Creation of focused virtual library based on various scaffolds (scaffold hoping)• Selection and extraction of library through clustering techniques• Selectivity profiling of compounds against several proteins• Filtering and manipulation of large library• Molecular dynamics and quantum mechanic/semi-empirical calculations• Custom software development
  4. 4. The Molecular Forecaster Approach• Accurate software – Software/methods combine advanced physics, biochemistry and chemical intuition to solve problems – Proprietary software: competitive pricing• Service – High level of protection and confidentiality for you data – Never retain any IP on the molecules developed
  5. 5. Service Contracts• Secure – High level of protection and confidentiality for you data – MFI Never retain any IP on the molecules developed• Quotes – Based on the preliminary evaluation of our software with the proposed project, we propose different scenarios for you to choose – We also define milestones and offer the option to opt-out at any time if the expected results are not reached – We are very flexible and always concerned by your entire satisfaction
  6. 6. Our in-house Software• FITTED docking program • Flexible protein • Displaceable water molecules • Automated covalent docking• PREPARE, SMART, ProCESS • Automated preparation of protein and ligand files• CONVERT: 2D to 3D conversion of small molecules• SELECT: compound similarity, extraction of focused highly diverse libraries or identification of analogues• REDUCE: filtering based on descriptors and functional groups• REACT: combinatorial chemistry in silico from user-defined chemical schemes• IMPACTS: sites of metabolism prediction program (CYP 450)• ACE: prediction of stereochemical outcome of reactionsNo third party licensing of software!
  7. 7. The Forecaster Platform J. Chem Inf. Model. 2012, 52, 210
  8. 8. Virtual Screening of Covalent POP Inhibitors• Prolyl OligoPeptidase involved in neurogenerative diseases (e.g. Alzheimer’s)• Reported covalent inhibitors have higher bioactivities than non covalent• FITTED: automatic detection of the formation of a covalent bond whenever possible• FITTED -guided discovery of active POP inhibitors• Fully automated and suitable for virtual high-throughput screening.• ZINC database of aldehyde and nitrile containing molecules was screened and hit molecule was further optimized. Virtually optimized compounds were synthesized and evaluated.They all inhibited the enzyme at the J. Med. Chem. 2009, 52, 6672cellular level at low nM concentrations J. Med. Chem. 2012, 55, 6306
  9. 9. Virtual Screening of HCV Polymerase Inhibitors• Challenging enzyme for docking methods• Validation experiments carried out with FITTED on two binding sites on HCV polymerase (allosteric and catalytic site)• Virtual screening on the Maybridge library seeded with known actives gave enrichment factors which were superior to the ones often observed with other available docking programs Top-scoring compounds (~ 1% of the Maybridge library) were purchased and screened in HCV polymerase assays, resulting in the identification of two compounds with IC50′s of 7 and 12 μM J. Chem. Inf. Model. 2008, 48, 902
  10. 10. Binding to G-quadruplex• A platinum supramolecular square as an effective G-quadruplex binder and telomerase inhibitor• Molecular modeling studies show the square arrangement of the four bipyridyl ligands• We demonstrate that this platinum square strongly binds to G- quadruplexes and can act as an inhibitor of telomerase• Docking and molecular dynamics studies was used to dock the platinum complex to the G-Quadruplex and predict the most favorable binding mode J. Am. Chem. Soc. 2008, 130, 10040
  11. 11. Platinum(II) Phenanthroimidazoles for TargetingTelomeric G-Quadruplexes • Experimental analyses and molecular modeling showed that these complexes template and stabilize G-quadruplexes • DFT calculations showed a significant impact of the chlorine atom on the highest occupied molecular orbital (HOMO) of the complex • Comparison of the HOMOs of a) complex 1 and b) complex 6. The dark isosurfaces represent the HOMO of the complexes computed by DFT Chem. Med. Chem. 2012, 7, 85
  12. 12. Discovery of Vitamin D ReceptorAntagonists• Modeling studies indicate that antagonism arises from side chain rigidity, when compared to a more flexible saturated analogue, which interferes with H12 folding/alignment• Molecular dynamics followed by docking provided rationale about the binding mode and the observed potency J. Med. Chem. 2010, 53, 7461
  13. 13. Retinoic Acid Receptors • FITTED was first tested for its ability to extract actives molecules from a set of inactive decoys (similar inactives molecules) • Eleven known RAR active ligands were seeded in a set of 378 random carboxylates • FITTED was able to extract all the eleven ligands at the top of the ranking list • FITTED was then used to screen more than 55,000 ligands in a virtual screening fashion Unpublished results

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