Integrating Medicinal Chemistry and Computational Chemistry: The Molecular Forecaster Approach

Transcription

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

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 hopping) 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 IMPACTS: sites of metabolism prediction program (CYP 450) RESHAPES: 3D pharmacophore searching CONVERT: 2D to 3D conversion of small molecules SELECT: compound similarity, extraction of focused highly diverse libraries or identification of analogues FinDERS: searching substructures from large databases of chemicals. REDUCE: filtering based on descriptors and functional groups REACT: combinatorial chemistry in silico from user-defined chemical schemes 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 cellular level at low nm concentrations J. Med. Chem. 2009, 52, 6672 J. Med. Chem. 2012, 55, 6306

9 Prediction of Sites of Metabolism of Xenobiotics by P450s IMPACTS : In-silico Metabolism Prediction by Activated Cytochromes and Transition States. Computational tool that combines docking to metabolic enzymes, transition state modeling and rule-based substrate reactivity prediction to predict the site of metabolism (SoM) of xenobiotics. Its application to sets of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates and comparison to experts predictions demonstrates its accuracy and significance. IMPACTS identified an experimentally observed SoM in the top 2 predicted sites for 77% of the substrates. J. Chem Inf. Model. 2012, 52, 2471

10 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

11 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

12 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

13 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

14 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