S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician

Pharmacogenomics & Drug Design

Fragment Based Drug Design (FBDD)Fragment Based Drug Design (FBDD)

S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician

S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA

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Definition

By definition, de novo means “from the new” andinvolves the design of complex new molecules from smaller constituent partsThe typical fragment-based project begins with an“efficient” binder, which may not be a particularly tightbinder.

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 approachesThese 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

FBDD Approaches: Fragment Elaboration

Lead optimisationby fragmentelaboration and/orrecombination

Fragment libraryscreening

FBDD Approaches: Fragment Fusion

Fragment libraryscreening

Lead optimizationby fragmentcombination andscaffold hopping

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

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

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 μM affinity

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, andHydrogen 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

FBDD-the process

Fragment Elaboration

If more than one fragment is found to bind in an active site, thesefragments 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 laboratoriesusing the same fragment in identical modes mightreasonably be expected to ‘discover’ similar chemicalseries.SBDD-the future of FBDD

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