Hierarchic Informational Technology for Effective Molecular Design of Drug Agents

1. Hierarchic Informational Technology for Effective Molecular Design of Drug Agents From Science to Business Workshop 11-12 October 2006, Kyiv Victor E. Kuz’min +380-48-7225127 victor@farlep.net A.V. Bogatsky Phys. – Chem. Institute NAS of Ukraine Odessa

2. Talk outline Introduction Problem Description & Market Need Solution of Problem The Principle Steps of QSAR Brief HIT4QSAR description The Principle Steps of HIT4QSAR Experimental results 1 – 4 The unique and overwhelming HIT4QSAR advantages Advantages ofHIT4QSAR Relatively Competitive Approaches and Models The comparative analysis of efficacy of HIT4QSAR Competitive Matrix Stage of development of HIT4QSAR Targeted Market Segment Opportunity for joint work Contact information

3. Proprietary information statement • The technology material presented in this talk is available for licensing or joint product development. • None of the slides contain any confidential or proprietary information which would prevent patenting the technology.

4. Introduction "There are 10180possible compounds, 1018likely drugs, 107known compounds, 106commercially available compounds, 106compounds in corporate databases, 104compounds in drug databases, 103commercial drugs and 102profitable drugs" A. Weininger J. Chem. Inf. Comput. Sci., 37, 138 (1997)

5. Problem Description & Market Need DRUG DISCOVERY Ooms, F. Curr. Med. Chem. 2000, 7, 141-158 • How to decrease the set of the explored compounds? • How to accelerate the drug discovery process? • How to reduce financial expenditure?

6. Solution of Problem Quantitative Structure – Activity Relationship Software for QSAR CoMFA - Comparative Molecular Field Analysis (Tripos, USA) CoMSiA - Comparative Molecular Similarity Analysis (Tripos, USA) HQSAR - Holographic QSAR (Tripos, USA) EVA - Eigenvalue Analysis (Tripos, USA) CODESSA – Comprehensive Descriptors for Structural and Statistical Analysis (SemiChem, USA) Cerius2 - QSAR software (Accelrys, USA) EMMA – Effective Modelling of Molecular Activity (MSU, Russia) DRAGON - QSAR software (MU, Italy) HIT4QSAR – Hierarchical Informational Technology for QSAR (PCI NAS, Odessa, Ukraine)

7. Structures of new compounds Selection of structural parameters promotes the activity The Principle Steps of QSAR QSAR A = f(S1,S2,S3,…,SM) Verification of model

8. Brief HIT4QSAR description

9. Selection of molecular fragments that determine the Activity Estimationof contribution to interaction“molecule-biological target” The principle steps of HIT4QSAR Molecular Designof New Perspective Compounds with High Activity Hypothesesabout mode of of Biological Activity

10. Experimental results 1 ANALYSIS OF THE ANTI-INFLUENZA ACTIVITY (LgTID50) Training set Statistical characteristics of QSAR models

11. Experimental results 2 Color-coding of molecular fragments with standpoint of their influence on the activity - enhance the activity - decrease the activity

12. Experimental results 3 The relative influence of molecular fragments on value of activity, lgTID50

13. Molecular design of structures with potentially high anti-influenza activity

14. Experimental results 4 The relative influence of some physical and chemical factors into the activity estimated from the HIT4QSAR models

15. The unique and overwhelming HIT4QSAR advantages are: • simplex representation of molecular structure (SiRMS), Fourier transformation of structure parameters spectrum, characteristics of molecular informational field – all of them is providing universality, diversity and flexibility of description for compounds of different structural types; • HIT4QSAR that depending on the concrete aims of research allows to construct the optimal strategy of QSAR models generation, avoiding at the same time the superfluous complication that doesn't results in the adequacy increase. • on the every stage of HIT4QSAR usage we can determine the molecular structure featuresthat are important for the studied activity, and exclude the rest. It shows unambiguously the limits of expedient QSAR models complication and allows not to waste superfluous resources for needless calculations.

16. Advantages ofHIT4QSAR Relatively Competitive Approaches and Models (CoMFA, CoMSiA, HASL, CODESSA, EMMA, DRAGON, HQSAR) • Unlike HIT4QSAR, a majority of descriptors in CODESSA, EMMA, DRAGON have interpretation difficulties and little suitable for molecular design. These approaches are applicable, mainly, for an activity prediction. • HIT4QSAR does not have the restrictions of such well-known and widely used approaches as CoMFA (Comparative Molecular Field Analysis), CoMSIA, and HASL, usage of the lasts is limited in the structurally homogeneous set of molecules and only one conformer. • HIT4QSAR has not the HQSAR restrictions (only topological representation of molecular structure) and lacks (ambiguity of descriptors formation when procedure of hashing of molecular holograms is realized). Besides, on the contrary to HQSAR, in SiRMS, different physical and chemical properties of atoms (charge, lipophilicity, etc.) can be taken into account.

17. The comparative analysis of efficacy of HIT4QSAR Angiotensin Converting Enzyme (ACE) inhibitors Results fromSutherland J.J.; O’Brien L.A.; Weaver D.F. A Comparison of Methods for Modeling Quantitative Structure—Activity Relationships. J. Med. Chem. 2004, 47, 5541-5554 CoMFA - Comparative Molecular Field Analysis CoMSiA - Comparative Molecular Similarity Indices Analysis EVA - Eigenvalue Analysis HQSAR - Holographic QSAR Cerius2 - QSAR software Work set – 76 compounds Test set – 38 HIT4QSARon Base Simplex Representation of Molecular Structure Q2 R2 Our models are more adequately and have more high statistical rates.

18. Competitive Matrix

19. Stage of development of HIT4QSAR HIT4QSAR is realized as software, tested, available for demonstration, field testing was carried out. Here are presented high activity compounds, which was designed by means of developed HIT4QSAR

20. Targeted Market Segment • The developed HIT4QSAR allows to decide any tasks“structure – property”. On the basis of this technology, carry out of molecular design of various compounds is possible with the complex of useful properties. We have experience of molecular design of perspective drugs (antiviral, antitumor, psychotropic, antimicrobial, anti-inflammation, etc), pesticides, optical materials, complexones, food supplements, quenching agents, etc.The results of the use of our technology can be interesting and useful for all, who carry out development of new drugs, materials, reagents, etc. • Potential consumers of HIT4QSAR are pharmaceutical companies and developers of software for QSAR. • Cost of project that related to the prediction and design of new drugs, substances and materials depends on the amount of concrete tasks, presence and content of information for the construction of training set, special requirements to the results.Rough estimate – 10 000 $ for:test set 30-50 compounds, level of modeling - 2D, term of contract - 1 month

21. Opportunity for joint work • We seek a potential clients, which need the results of the use of our technology.We are ready to vend theservice – structureoptimization, molecular design, prediction of new compounds with complex of demand properties – by means of HIT4QSAR. • We are ready for collaboration with colleagues – chemists- synthesist and specialists of investigation different properties of substances (biologist, virologists, pharmacologist,etc) for carry out joint projects.

22. Contact information Doctor of chemical science Victor E. Kuz’min Head of laboratory on theoretical chemistry A.V. Bogatsky Phys. – Chem. Institute NAS of Ukraine, Odessa +380-48-7225127 victor@farlep.net Thank you for attention