Integrating Medicinal Chemistry and Computational ... ?· Integrating Medicinal Chemistry and Computational…

Download Integrating Medicinal Chemistry and Computational ... ?· Integrating Medicinal Chemistry and Computational…

Post on 05-Jun-2018

213 views

Category:

Documents

0 download

Embed Size (px)

TRANSCRIPT

  • Integrating Medicinal Chemistry and Computational Chemistry:

    The Molecular Forecaster Approach

    Molecular Forecaster Inc.

    www.molecularforecaster.com

  • 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

  • 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

  • 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

  • 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

  • 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!

  • The Forecaster Platform

    J. Chem Inf. Model. 2012, 52, 210

  • Virtual Screening of Covalent POP Inhibitors

    Prolyl OligoPeptidase involved in neurogenerative diseases (e.g. Alzheimers)

    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.

    J. Med. Chem. 2009, 52, 6672 J. Med. Chem. 2012, 55, 6306

    Virtually optimized compounds were synthesized and evaluated.

    They all inhibited the enzyme at the cellular level at low nM concentrations

  • 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

  • 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 IC50s of 7 and 12 M

    J. Chem. Inf. Model. 2008, 48, 902

  • 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

  • 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

  • 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

  • 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

Recommended

View more >