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

1. Integrating Medicinal Chemistry
and Computational Chemistry:
The Molecular Forecaster Approach
Molecular Forecaster Inc.
www.molecularforecaster.com

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. 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. 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. 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. 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 reactions
No third party licensing of software!

7. The Forecaster Platform
J. Chem Inf. Model. 2012, 52, 210

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, 6672
cellular level at low nM concentrations J. Med. Chem. 2012, 55, 6306

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. 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. Platinum(II) Phenanthroimidazoles for Targeting
Telomeric 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. Discovery of Vitamin D Receptor
Antagonists
• 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. 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