GQSAR presentation


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GQSAR is a breakthrough patent pending methodology that significantly enhances the use of QSAR as an approach for new molecule design. As a predictive tool for activity, this method is significantly superior to conventional 3D and 2D QSAR. Here we explain application of GQSAR for optimizing compounds in congeneric series.

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GQSAR presentation

  1. 1. (GQSAR, Group based QSAR), A fragment basedapproach: Mitigating Interpretation Challenges in QSAR! 1
  2. 2. Agenda Brief about QSAR A way forward - Why GQSAR GQSAR Method Case Studies Comparing GQSAR References Q&A © VLife Sciences Technologies Pvt. Ltd. 2 All rights reserved
  3. 3. Brief about QSARIt is an integral part of rational drug discovery process Response (y) = f(x1,x2,x3……….xp)Objectives of QSAR To identify molecular features/properties responsible for variation in desired response. To understand mechanism of molecular interaction based on the identified important features/properties governing desired response To build a mathematical model which can be used to predict desired response of new molecules. To generate clues for designing new molecules having promise of superior activity. © VLife Sciences Technologies Pvt. Ltd. 3 All rights reserved
  4. 4. Continued...QSAR data Activity Descriptors Ranging from 0D, 1D, 2D, 3D, 4D Y1 X11 X12 X13 . . . X1pWhere n > 20, Y normal distributed Y2 X21 X22 X23 . . . X2p Y3 X31 X32 X33 . . . X3p . . . . . . . . . . . . . . . . Molecules . . . . . . . . Yn Xn1 Xn2 Xn3 . . . Xnp © VLife Sciences Technologies Pvt. Ltd. 4 All rights reserved
  5. 5. Continued...Type of Descriptors • Hansch MethodSubstituent based • Free Wilson Approach • Conformation IndependentWhole molecule - 2D • Conformation DependentWhole molecule - • Conformation and Alignment 3D Dependent © VLife Sciences Technologies Pvt. Ltd. 5 All rights reserved
  6. 6. Continued... Qualities of useful QSAROffering site specific clues for novel molecule designFlexibility to study molecular sites of interestEase of interpretationModel to predict activity of novel moleculeFast descriptor calculation © VLife Sciences Technologies Pvt. Ltd. 6 All rights reserved
  7. 7. A way forward – why GQSAR ?Conventional 2D QSAR Enables fast calculation of molecular descriptors Offers basis for searching new candidates from database of already synthesized molecules Interpretation of model is complex Offers no design (site specific)clues3D QSAR Offers ease of model interpretation Offers clues for better design of molecules Tedious process Results dependent on selection of conformers and alignment of molecules © VLife Sciences Technologies Pvt. Ltd. 7 All rights reserved
  8. 8. Continued...why GQSAR??QSAR – Molecular Descriptors Molecular Sites to optimize a particular chemical propertyMagnitude and Direction O count Mol. logP logP wt. ? Mol. wt. Mol.wt. logP Mol. wt. ? R3 logP wt. ? Mol. Mol.wt. logP R4 R2 logP logP wt. Mol. ? R5 No. of HBA R1 logP wt. Mol. ? heavy atoms N N HBD H 2 NO 2 S Interacting sites to be optimized simultaneously through corresponding chemical properties © VLife Sciences Technologies Pvt. Ltd. 8 All rights reserved
  9. 9. Group Based QSAR Method[GQSAR]Deals with molecular fragment/group based descriptors to build QSAR modelFragments are derived by applying specific chemical rules by fragmentationalong:  Specific bonds  Bonds on the ring fusion  Regions of molecules that can be separated from common structural feature such as atom, bond and ring  Any pharmacophoric feature such as HBA , HBD, hydrophobic group, charged group etc. GQSAR fragment descriptors should not be confused with already existing 2- Dimensional topological Descriptor © VLife Sciences Technologies Pvt. Ltd. 9 All rights reserved
  10. 10. Continued… GQSAR Fragment C Fragment B Fragment AIdentify important molecular sites and their corresponding properties to aidin novel molecule design © VLife Sciences Technologies Pvt. Ltd. 10 All rights reserved
  11. 11. Continued… Group Descriptors GQSAR, we are calculating these descriptors for each molecular fragments and not for the whole molecule 2D DescriptorsHBA, HBD, rotatable bonds, chi indices, valence-chi indices, electro-topological indices, substituent constants etc. Fragment A Fragment B Fragment CVolume, surface area, dipole moment, moment of inertia, radius ofgyration, polar surface area etc. 3D Descriptors © VLife Sciences Technologies Pvt. Ltd. 11 All rights reserved
  12. 12. Continued… Group Descriptors Cross Terms D1A D1A x D2 B Fragment A D1 D1A - D2 B D1A + D2 B Fragment B D2 D1A / D2 B D2 B f (D1A,D2 B ) DescriptorsInclusion of Interactions of various fragments…. © VLife Sciences Technologies Pvt. Ltd. 12 All rights reserved
  13. 13. GQSAR Modeling Methods Variable selection methods:  Stepwise forward  Stepwise forward-backward QSARpro software offers a very  Stepwise backward unique facility to couple any of  Simulated annealing method  Genetic algorithm the variable selection methods, Statistical model building methods: with any statistical model  Multiple regression building method  Principal component regression  Partial least squares regression  k-nearest neighbor  Neural Networks © VLife Sciences Technologies Pvt. Ltd. 13 All rights reserved
  14. 14. GQSAR – Molecular Fragmentation Congeneric series Non-congeneric series R3 D B R4 R2 3 1 A R5 R1 N N Y X H2NO 2S CSubstituted 1,5-diphenylpyra z ole as Fragmentation of AKT1 inhibitorsCox-2 Inhibitors © VLife Sciences Technologies Pvt. Ltd. 14 All rights reserved
  15. 15. GQSAR Case Study I Congeneric series R3 R4 R2 R5 R1 N N H2NO 2S Substituted 1,5-diphenylpyra z ole as Cox-2 InhibitorsDesiraju, G. R.; Gopalakrishnan B.; Jetti, R. K. R.; Raveendra, D.; Sarma, J. A. R. P.; Subramanya, H. S., Molecules 2000, 5, 945-955 © VLife Sciences Technologies Pvt. Ltd. 15 All rights reserved
  16. 16. COX-2 GQSAR Model Fragmentation of molecule based on substitution sites R1, R2, R3, R4 and R5 Calculation of simple 2D descriptors like log P, molecular weight, electro- topological index, molecular refractivity, Baumann alignment independent topological descriptors etc. QSARpro software allows the user to calculate and use more than 1000 descriptors For model validation, a training set of 25 and test set of 5 molecules were considered as reported in the paper Model building using stepwise variable selection and multiple regression and PLS regression methods © VLife Sciences Technologies Pvt. Ltd. 16 All rights reserved
  17. 17. COX-2 Dataset – Model Results Parameters QSAR GQSARTrain/Test 25/5 25/5No. of Descriptors 8 12Optimum Components 6 4r2 0.93 0.93CV_r2 (q2) 0.75 0.86Pred_r2 0.86 0.90F-test 41.12 67.46Prob. Of Significance <0.00001 <0.00001SEE 0.36 0.34CV_SE 0.70 0.50Pred_SE 0.22 0.17Zscore_CV 3.48 4.02Best_ran_CV -0.77 -1.28α_ran_CV <0.001 <0.001 © VLife Sciences Technologies Pvt. Ltd. 17 All rights reserved
  18. 18. COX-2 GQSAR – Descriptor Contribution Plot © VLife Sciences Technologies Pvt. Ltd. 18 All rights reserved
  19. 19. COX -2 GQSAR Prediction PlotGQSAR has offered us a better model as far as the internal and external validations are concerned. © VLife Sciences Technologies Pvt. Ltd. 19 All rights reserved
  20. 20. COX- 2 GQSAR Interpretation O count logP Mol.wt. R3 Mol.wt.No. of heavy logP R4 R2atoms Molar R5 No. of heavy atoms Refractivity R1 N N H NO S 2 2 © VLife Sciences Technologies Pvt. Ltd. 20 All rights reserved
  21. 21. GQSAR Flow Set of molecules with reported activity or property Define rules to fragment molecules Create fragment for each molecule in the set Calculate molecular fragment descriptors Apply variable selection and model building method Validate/Finalize GQSAR modelInterpret finalized model and utilize direction to design novel molecules Predict activity of designed molecule using developed model © VLife Sciences Technologies Pvt. Ltd. 21 All rights reserved
  22. 22. Addressing inverse QSAR problem  GQSAR – Sites to optimize along with a particular chemical property  Identify R1-R5 ranges using active molecules properties ranges in the dataset – using kNN and regression method R3 R4 R2 Search Similar R5 N Fragments within N R1 Applicability domain H2 NO2S Combining New molecules withFragment Database fragments R1-R5 desired activity that satisfy ranges © VLife Sciences Technologies Pvt. Ltd. 22 All rights reserved
  23. 23. QSAR Methods - Comparison Substituent 2D QSAR 3D QSAR GQSAR BasedConformation Independent Y Y N YAlignment Independent Y Y N YFast Calculation of N Y Y YDescriptorInteraction Descriptor N N N YSite Specific Clues for NCE N N N YDesignScreening of Large Y Y N YDatabasesGeneration NCE Library Y N Y Y © VLife Sciences Technologies Pvt. Ltd. 23 All rights reserved
  24. 24. References GQSAR is patented by VLife Sciences Technologies Pvt. Ltd. References  "Group B ased QSAR (G-QSAR) : Mitigating Interpretation Challenges in QSAR”, QSAR & Combinatorial Science, 28(1),36–51(2009)  "A Comprehensive Structure-Activity Analysis of Protein Kinase B-alpha (Akt1) Inhibitors“, Journal of Molecular Graphics and Modelling, (2010) doi: 10.1016/j.jmgm.2010.01.007 For more information & QSARpro trial: © VLife Sciences Technologies Pvt. Ltd. 24 All rights reserved
  25. 25. VLife Sciences Technologies Pvt Ltd 101-102 Pride Purple Coronet, Baner Road, Pune 411 045 (MS) India Tel / Fax : +91 20 2729 1590/1 Email : Copyright © 2005 VLife Sciences Technologies Pvt. Ltd. All Rights Reserved. 25VLife Sciences, VLife Logo ,and all other VLife product names and slogans are trademarks or registered trademarks of VLife Sciences Technologies Pvt. Ltd.