IU Chemical Informatics Journal Club

Author: Wendy A. Warr
Source: Journal of Computer-Aided Molecular Design (2009) 23:453–458 DOI 10.1007/s10822-009-9292-1

This paper provides information about Fragment Based Drug Discovery (FBDD) that author has received from Rob Hubbard of Vernalis and Mark Murko of Vertex. The paper contains a list of selected FBDD companies like Vernalis. It states that the low cost of market entry has led to the formation of many specialized companies, and few universities and research institutes have also adopted FBDD. The enthusiasm, ability and requirements of big pharma companies are discussed in the paper. Also, the screening methods for fragments, examination of novel targets, optimization of hits and finally future prospective are mentioned in brief.

NMR and X-ray crystallography techniques had been used for screening fragments. NMR and X-ray analyses provide structural information about the binding site of a hit. Surface plasmon resonance (SPR) is a relatively recent technology for distinguishing good hits from ones which bind nonspecifically. SPR has the advantage of providing quantitative dynamics data on the binding interaction, such as binding constants, which are complementary to the structural information from X-ray and NMR screens. Some companies have also used thermal methods (isothermal titration calorimetry or protein thermal unfolding), mass spectrometry (MS) and high concentration bioassays. However it’s resulted, in some cases, the use of multiple methods will probably be necessary.

FBDD approaches enable the efficient development of novel leads as these technologies are design intensive rather than resource intensive, as compared to HTS. HTS sometimes fails to find hits that interfere with new targets, such as protein–protein interaction surfaces. FBDD can also find new binding modes and allosteric sites. The only problem of FBDD lies in ligand specificity that fragment-based approaches identify and characterize only ‘‘hot spots’’, i.e. the regions of a protein surface that are major contributors to the ligand binding free energy. Unfortunately many binding sites in the active site that are responsible for target specificity and/or selectivity are not included in these ‘‘hot spots’’. It is stated that a fragment screen provides a rapid and reliable means of interrogating a protein target for druggability before investing in further discovery research. Structure-based drug design (SBDD) can then be used in optimization of the fragment. Once a hit has been found, it is optimized into a lead by one of three approaches: linking (to find second site fragments), growing (by structure guided medicinal chemistry or by using the fragment binding motif to search for similar compounds that can be purchased), or merging. Efficiency and potency are the criteria used in optimization but we also need to consider lipophilicity, polarity, charge, stability etc.

The big pharmaceutical companies that used to be critical are now bringing fragment-based approaches to the fore, having the required skill sets and requiring researchers from different disciplines. They are countering some problems by partnering with smaller biotechs. The complementary use of HTS and FBDD is a common theme in the larger companies. Author, here also, gives the opinions of few people from FBDD research sectors.

For next they are finding many new opportunities for new development, such as improving the novelty, structural diversity and physicochemical properties of fragment libraries, then plenty of scope for increasing the efficiency of fragment optimization, and further developments in modeling and computational chemistry including methods for predicting binding modes, and examination of entropy and desolvation. One challenge is deciding which fragments to progress, other than using the subjective decisions of a medicinal chemist. Most of the publications and presentations on FBDD are remarkably positive but many are produced by advocates of the technology or by authors with a business bias.