G. Narahari Sastry Molecular Modeling Group Organic Chemical Sciences Indian Institute of Chemical Technology Hyderabad

2. Integration of Chemoinformatics and Bioinformatics

3. Biological Structure

4. Much About Structure

5. Bottlenecks in developing Structure � Function Relationships

10. High Resolution Structural Biology Determine atomic structure Analyze why molecules interact

11. To get a glimpse of the Structural Biology approach, I will now show you an example from the cancer research in our laboratory. 2nd SLIDE- TITLE I will describe how taking a snapshot of the atomic structure of two molecules at the moment when they are communicating can be used to understand how an extremely potent anticancer agent is targeted to a precise location on a molecule of DNA. � �First item In this picture the green and pink sticks represent the atomic structure of one small portion of a DNA sequence from a gene. If you look carefully, you can see the well-known features of the intertwined DNA double helix in these atoms. 2nd and 3rd item The blue sticks that are placed within the cloud represent the atoms of the anticancer drug duocarmycin SA. The simple stick representation is used to help visualize the molecules but in fact, the cloud is a much more realistic representation of the atoms. 4th item This picture show how well the drug and the DNA fit together, like a key in a lock. This gives a graphic representation of one of the key elements of designing a drug: the need to make the shape of the drug complementary to the target. Many of the other key elements needed for drug design require an even deeper level of inspection of the structure of the molecule. Next items- show small box and build the new larger box including the picture inside We will zoom in closer to the atoms for a better view. At this level of magnification we can examine the details of the interactions between each atom in the drug and DNA target. Next item- label �atomic interactions� In this picture, the critical information is where the surface of the clouds come close to the sticks. It is here at this level of ultra magnification where we can really fine tune the details of the drug to generate the specificity that is needed to ensure there are no side effects to a drug. Lights up to talk Structural Biology is providing a whole new strategy for the design of drugs with higher specificity and fewer side effects than has been achievable with traditional approaches where hundreds or even thousands of random drug candidates must be scanned. There is tremendous excitement in univeristies and the pharmaceutical industry because this structure-based drug design strategy will save huge amounts of time and money in the effort to develop new therapeutics for the clinic. I look forward with anticipation to the opening of the new building when we will be placed in close juxtaposition with many of the most exciting laboratories on campus. I hope I have given you a sense of our excitement over the vast possibities of using the structural biology approach for advancing medicine and biology.To get a glimpse of the Structural Biology approach, I will now show you an example from the cancer research in our laboratory. 2nd SLIDE- TITLE I will describe how taking a snapshot of the atomic structure of two molecules at the moment when they are communicating can be used to understand how an extremely potent anticancer agent is targeted to a precise location on a molecule of DNA. � �First item In this picture the green and pink sticks represent the atomic structure of one small portion of a DNA sequence from a gene. If you look carefully, you can see the well-known features of the intertwined DNA double helix in these atoms. 2nd and 3rd item The blue sticks that are placed within the cloud represent the atoms of the anticancer drug duocarmycin SA. The simple stick representation is used to help visualize the molecules but in fact, the cloud is a much more realistic representation of the atoms. 4th item This picture show how well the drug and the DNA fit together, like a key in a lock. This gives a graphic representation of one of the key elements of designing a drug: the need to make the shape of the drug complementary to the target. Many of the other key elements needed for drug design require an even deeper level of inspection of the structure of the molecule. Next items- show small box and build the new larger box including the picture inside We will zoom in closer to the atoms for a better view. At this level of magnification we can examine the details of the interactions between each atom in the drug and DNA target. Next item- label �atomic interactions� In this picture, the critical information is where the surface of the clouds come close to the sticks. It is here at this level of ultra magnification where we can really fine tune the details of the drug to generate the specificity that is needed to ensure there are no side effects to a drug. Lights up to talk Structural Biology is providing a whole new strategy for the design of drugs with higher specificity and fewer side effects than has been achievable with traditional approaches where hundreds or even thousands of random drug candidates must be scanned. There is tremendous excitement in univeristies and the pharmaceutical industry because this structure-based drug design strategy will save huge amounts of time and money in the effort to develop new therapeutics for the clinic. I look forward with anticipation to the opening of the new building when we will be placed in close juxtaposition with many of the most exciting laboratories on campus. I hope I have given you a sense of our excitement over the vast possibities of using the structural biology approach for advancing medicine and biology.

14. Structure Based Drug Design

16. Study of protein crystals give the details of the �lock�. Knowing the �lock� structure, we can DESIGN some �keys�.

17. Variations on the Lock and Key Model

20. 3D Structure of the Complex

21. Building Molecules at the Binding Site

25. Molecular Docking The process of �docking� a ligand to a binding site mimics the natural course of interaction of the ligand and its receptor via a lowest energy pathway. Put a compound in the approximate area where binding occurs and evaluate the following: Do the molecules bind to each other? If yes, how strong is the binding? How does the molecule (or) the protein-ligand complex look like. (understand the intermolecular interactions) Quantify the extent of binding.

26. Molecular Docking (contd�) Computationally predict the structures of protein-ligand complexes from their conformations and orientations. The orientation that maximizes the interaction reveals the most accurate structure of the complex. The first approximation is to allow the substrate to do a random walk in the space around the protein to find the lowest energy.

27. Algorithms used while docking Fast shape matching (e.g., DOCK and Eudock), Incremental construction (e.g., FlexX, Hammerhead, and SLIDE), Tabu search (e.g., PRO_LEADS and SFDock), Genetic algorithms (e.g., GOLD, AutoDock, and Gambler), Monte Carlo simulations (e.g., MCDock and QXP),

28. Some Available Programs to Perform Docking Affinity AutoDock BioMedCAChe CAChe for Medicinal Chemists DOCK DockVision FlexX Glide GOLD Hammerhead PRO_LEADS SLIDE VRDD

31. Examples of Docked structures

33. Rigid Docking Shape-complementarity method: find binding mode(s) without any steric clashes Only 6-degrees of freedom (translations and rotations) Move ligand to binding site and monitor the decrease in the energy Only non-bonded terms remain in the energy term Try to find a good steric match between ligand and receptor

34. Describe binding site as set of overlapping spheres Both the macromolecule and the ligand are kept rigid; the ligand is allowed to rotate and translate in space In reality, the conformation of the ligand when bound to the complex will not be a minima.

35. The DOCK algorithm in rigid-ligand mode

36. Flexible Docking Dock flexible ligands into binding pocket of rigid protein Binding site broken down into regions of possible interactions

37. Then dock the molecule into pocket by matching up interactions with ligand Uses �random� translation, rotation, and torsion, and look for a better binding mode.

38. Even though we have considered the ligand to be flexible, the active site was kept as a rigid structure. The side chains of the protein in the vicinity of the active site should be flexible, but computationally more expensive.

39. Incremental Construction (FlexX) A piecewise assembly of ligand within the active site. Generate rigid fragments by scissoring the rotatable bonds of known ligands. Dock the fragments one by one starting from the larger fragment Assemble the whole ligand by reconnecting them and repeat the docking process

41. Detailed calculations on all possibilities would be very expensive The major challenge in structure based drug design to identify the best position and orientation of the ligand in the binding site of the target. This is done by scoring or ranking of the various possibilities, which are based on empirical parameters, knowledge based on using rigorous calculations

42. Exact Receptor Structure is not always known

43. Receptor Mapping The volume of the binding cavity is felt from the ligands which are active or inactive. This receptor map is derived by looking at the localized charges on the active ligands and hence assigning the active site.

44. Receptor Map Proposed for Opiate Narcotics(Morphine, Codeine, Heroin, etc.)

58. Outlook Molecular modeling first introduced in the pharmaceutical industries in the early 70�s have raised probably unrealistic hopes such as it can �do it all�. But it took quite a while before it could deliver No doubt, with the ever-expanding new powerful methods available, today�s modelers have the requisite potential to bring real benefits to pharmaceutical industry.

59. Molecular Modeling and Computational Chemistry are essential to understand the molecular basis for biological activity and has Tremendous Potential to aid Drug Discovery A healthy interaction between computational chemists and pharmaceutical industry seem indispensable.

60. Structure Based Drug Design is an extremely important tool in the computer aided drug design. I Hope that you are convince!