Fragment based drug designing strategies

1. S.Prasanth Kumar, Bioinformatician Pharmacogenomics & Drug Design Fragment Based Drug Design (FBDD) S.Prasanth Kumar, Bioinformatician S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA www.facebook.com/Prasanth Sivakumar FOLLOW ME ON ACCESS MY RESOURCES IN SLIDESHARE prasanthperceptron CONTACT ME [email_address]

2. Definition By definition, de novo means “ from the new ” and involves the design of complex new molecules from smaller constituent parts The typical fragment-based project begins with an “ efficient” binder , which may not be a particularly tight binder.

3. Why FBDD ? High-throughput screening (HTS) of pre-existing compounds in a variety of pharmacological assays is still the most widely used approach to hit discovery . Half of all HTS screens fail to deliver appropriate chemical starting points for new discovery programmes. Reasons: the non drug-like compounds present in many chemical archives assembled by random combinatorial chemistry approaches These compounds cannot be optimized into development candidates It is usually more efficient to start discovery from creating new target-focused libraries of ‘lead-like’ compounds which can be more readily optimized

4. FBDD Approaches: Fragment Elaboration Lead optimisation by fragment elaboration and/or recombination Fragment library screening

5. FBDD Approaches: Fragment Fusion Fragment library screening Lead optimization by fragment combination and scaffold hopping

6. FBDD-the process Rule-of-3 compliant Fragment library Optimised for sensitivity Biological Assay High-concentration screening Hit Structure-guided hit elaboration Traditional lead optimisation

7. From Fragments to Drugs Lead compound derived based on fragment hits Bcl-xL with natural peptide bound By NMR Structure of clinical candidate ABT-737

8. Fragment-based design series Overlay of virtual screening hit and lead compound virtual screening hit Intermediate compound similar to the virtual screening hit that confirmed the predicted binding mode Lead compound with 0.021 μ M affinity

9. FBDD-the process The generation of a suitable Fragment Library fragments usually comply with the ‘ Rule of 3’ (Ro3) fragments should have MW > 300, LogP > three, and Hydrogen bond donors & acceptors >3 Ligand efficiency (LE) can be regarded as the average binding energy per atom or per mass unit of the structure. Fragments having high LEs can be selected at both at the start of and during the FBDD process Fragment Screening Techniques : XRD & NMR

10. FBDD-the process Fragment Elaboration If more than one fragment is found to bind in an active site, these fragments may be chemically linked to form a larger moiety One apparent disadvantage of the FBDD approach – when small, generic fragments are used as design ‘seeds’ – lies in the uniformity of the process. Two laboratories using the same fragment in identical modes might reasonably be expected to ‘discover’ similar chemical series. SBDD-the future of FBDD

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