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    Yunhan Chu defended their PhD thesis on developing methods for de novo design of functional drugs and catalyst compounds using an open source software called GeneGear. The thesis outlined GeneGear's evolutionary algorithm approach to de novo design, including building block representation, scoring functions, and applications in drug design against HIV protease and catalyst design for olefin metathesis. It also discussed incorporating a knowledge-based bias filter to constrain the search space and improve results by filtering out chemically insensible structures during evolution.

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    PhD Defense CYH

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    Yunhan Chu defended their PhD thesis on developing methods for de novo design of functional drugs and catalyst compounds using an open source software called GeneGear. The thesis outlined GeneGear's evolutionary algorithm approach to de novo design, including building block representation, scoring functions, and applications in drug design against HIV protease and catalyst design for olefin metathesis. It also discussed incorporating a knowledge-based bias filter to constrain the search space and improve results by filtering out chemically insensible structures during evolution.

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    90 views34 pages

    PHD Defense CYH

    Uploaded by

    Yunhan Chu
    Yunhan Chu defended their PhD thesis on developing methods for de novo design of functional drugs and catalyst compounds using an open source software called GeneGear. The thesis outlined GeneGear's evolutionary algorithm approach to de novo design, including building block representation, scoring functions, and applications in drug design against HIV protease and catalyst design for olefin metathesis. It also discussed incorporating a knowledge-based bias filter to constrain the search space and improve results by filtering out chemically insensible structures during evolution.

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    of 34

    Development of Methods for de novo Design of Functional Drugs and Catalyst Compounds

    PhD thesis defense

    Yunhan Chu
    Department of Chemistry, Norwegian University of Science and Technology (NTNU)

    21 June 2011

    Outline
    Introduction Overview of GeneGear for de novo design Evolutionary de novo drug design by GeneGear Evolutionary de novo coordination catalyst design by GeneGear A knowledge-based approach of GeneGear for constraining de novo EA search space Conclusions Acknowledgements

    21 June 2011

    21 June 2011

    How to explore chemical space ?

    Exploring known chemical space High Throughput Screening (HTS) Virtual Screening (VS) Exploring novel chemical space De novo design Using computer to produce novel molecular structures with desired properties by taking chemical space as a source

    21 June 2011

    Exploring chemical space by de novo design


    De novo Design How to sample chemical structures Molecular representation Building blocks Structural operations How to evaluate chemical structures Scoring function How to navigate through the space smartly Search algorithm

    Schneider G. et al., Nat. Rev. Drug Discov., 4:649663, 2005

    21 June 2011

    GeneGear An open source software for de novo design


    Advantages of GeneGear: Freedom in how the system is used, modified and extended Design of non-medicinal compounds

    21 June 2011

    GeneGear De novo design by an Evolutionary Algorithm (EA)

    21 June 2011

    GeneGear Building blocks (fragments)


    Molecules

    National Cancer Institute (NCI) diversity set (1990 molecules)

    Split

    Screen

    1151 fragments Fragments


    8 21 June 2011

    GeneGear Structural representation and operation

    Crossover
    1
    N N

    2
    N O

    3
    O N O N

    4
    N

    N N

    N N

    N F N N F F O N O Cl N N

    N F

    Cl N O N O N F N O N N O

    Cl N

    F O N O N

    Cl

    21 June 2011

    GeneGear Scoring function


    Receptor-based scoring
    Receptor-ligand binding free energy (affinity) Force-field based function (AutoDock) Empirical and knowledge-based function (Vina)

    Ligand-based scoring
    Molecular similarity Quantitative structure-activity relationship (QSAR)

    Multiobjective scoring
    f(p) = w1p1 + w2p2 + ... + wnpn

    10

    21 June 2011

    GeneGear application - Evolutionary drug design

    11

    21 June 2011

    Building a fragment library


    NCI diversity set (1990 molecules)

    Split

    Indinavir a HIV-1 protease inhibitor

    Screen

    1154 Fragments

    select
    12

    98 entries
    21 June 2011

    Design of HIV-1 protease inhibitor


    Ligand-based scoring (similarity) Receptor-based scoring (binding energy)

    Indinavir fragment set


    13

    NCI fragments
    21 June 2011

    Design of HIV-1 protease inhibitor - contd


    Multiobjective scoring (half-to-half weighted combination of receptor- and ligand-based strategy) Indinavir

    14

    21 June 2011

    GeneGear application - Evolutionary coordination catalyst design

    15

    21 June 2011

    Characteristics of coordination compound


    ionic neutral covalent bond dative bond ionic neutral metal Traditional de novo methods lack the following functions: To maintain and protect the coordination center To retrieve information associated with the coordination center To vary ligand groups in a restricted and meaningful manner To maintain possible characteristics of symmetric structures
    16 21 June 2011

    Representation of coordination compound


    Model Example

    lead c: core, t: trial, f: free

    17

    21 June 2011

    Assembly of coordination compounds

    Growing from a lead

    18

    21 June 2011

    Assembly of coordination compounds - contd


    Crossover of free parts

    Mutation of free part

    19

    21 June 2011

    Case study: Ruthenium catalyst for olefin metathesis

    Occhipinti G. et al., J. Am. Chem. Soc., 128:69526964, 2006.

    20

    21 June 2011

    A PLSR-based QSAR model for productivity

    PM6 optimized geometry of 14-electron active complex Q2=0.85, RMSECV=1.46 kcal/mol

    21

    21 June 2011

    Design of ruthenium catalysts


    L Cl Ru Cl

    R4 R2 R1 P Cl Ru Cl Cl Ru R3 R1 N

    R3 N

    R4 N

    R3 N

    R2 Cl

    R1

    R2 Cl

    Ru Cl

    22

    21 June 2011

    Fragment library design


    Lead library
    M R1 N N R2 NHC R1 R1 M P R3 R3 phosphine PAr3 NHC Cl NHC FF R2 P M M N R2 Cl R4 R3 R1 R2 M N R2 NHC H R2 R1 N M N R2 NHC HH R1 N

    C M

    P C R3

    M: Cl2Ru=CH2

    PR3

    R1 N

    Cl M

    R1 N N R2

    F F

    Free library

    2238 fragments (1155 side chains + 1083 scaffolds) derived from KEGG database

    23

    21 June 2011

    Parameter setup for EA experiments

    24

    21 June 2011

    Results of EA experiments evolution trends

    NHC

    > phosphine

    (Second gen.) (First gen.)

    Average of predicted productivity increases smoothly over generations

    25

    21 June 2011

    Results of EA experiments evolution trends (contd)

    26

    21 June 2011

    Results of EA experiments high active complex

    Complex
    N1 N2 N3

    DFT-calc. prod. (kcal/mol)


    2.8 1.9 4.8
    27 21 June 2011

    A knowledge-based approach of GeneGear for constraining de novo EA search space

    28

    21 June 2011

    Advantage and challenge of evolutionary algorithms in de novo design


    Advantages: Sampling a diverse chemical space Providing solutions to a wide range of objective problems Performing well in searching a large and complex space

    Challenge: Production of chemically insensible structures New molecules New molecules Bias filter Fitness function Discarded
    29 21 June 2011

    EA EA

    Fitness function

    Building a bias filter (BF)


    A bias molecule set to sample positive and negative examples. A set of structure descriptors to characterize the bias set structure space. A classification method to model the positive/negative boundary.

    30

    21 June 2011

    Application of bias filter (BF)


    bias filter 290 Factor Xa inhibitors, 77 descriptors k-NN (k = 2) ?

    Validation LOO CV Test set (145)

    Accuracy 94% 93%

    high lipophilic region, logP > 4.0

    31

    21 June 2011

    Results of BF and non-BF experiment

    logP > 4

    logP > 4.8

    32

    21 June 2011

    Conclusions
    De novo design is an important concept that allows a variety of computational knowledge, methods and tools to be implemented to explore chemical space. GeneGear has been tested to be effective at de novo design of functional molecules such as drugs by the implementation of a parallel EA framework. A new EA facilitated with special molecular representation and operations, quantum chemistry, and QSAR analysis is adapted for optimization of coordination compounds. A knowledge-based approach built with chemometrics, multivariate analysis, and machine learning is able to to constrain de novo EA searched space.

    33

    21 June 2011

    Acknowledgments

    The Department of Chemistry, NTNU is gratefully thanked for funding this research. Prof. Bjrn K. Alsberg is thanked for all his support and help. Members of Physical Chemistry group are thanked for their good advice.

    Thank you for your attention!

    34

    21 June 2011

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