Fragment Based Drug Design (FBDD) as an alternative approach to traditional lead identification

Fragment-based drug design (FBDD) has emerged as an alternative approach to traditional lead identification and is increasingly being used in large pharmaceutical settings to improve the drug discovery cycle. The results from these projects highlight the strength and shortcomings of FBDD in assisting drug discovery.

The variety of readily measurable parameters permits NMR to contribute efficiently to the ligand discovery process by assessing target drugability, initial hit identification via fragment-based drug design (FBDD) with screening of very small molecule (<300 dalton) libraries, pharmacophore identification, hit validation, hit optimization and potentially structure-based drug design. NMR can also be used to determine low resolution structures of target-ligand complexes for natively unstructured proteins or membrane proteins that are not amenable to crystallographic approaches.

Recently, early drug discovery has relied heavily on High Throughput Screening (HTS) to identify hit compounds for targets of interest. Because HTS is usually performed at lower concentrations (typically 10-30μM), the resulting hits frequently have properties more reminiscent of drugs than lead compounds. HTS hits are frequently large and complex molecules with poor solubility and ADME profiles. These hits are thus poor candidates for the initiation of a chemistry program because these programs usually result in molecules with increased molecular weight and logP.

Furthermore, the potency of ligands is not linearly related to increased molecular weight and in fact tapers off for compounds consisting of more than 15 nonhydrogen atoms, making the design of analogs to increase potency from an already large molecule more challenging. From their utilization in combinatorial chemistry to computational chemistry, the use of fragments or small molecules in drug design is not a new concept, but has only recently been considered at the earliest stages of drug discovery. 

It has been estimated that the number of potential drug molecules is of the order of 10¹⁰-10⁵⁰. However, for a given target system it is difficult to imagine high-throughput screening (HTS) performed with much more than 10⁶ compounds, especially considering that such endeavors would be very expensive and subject to a sizeable number of false positives and false negatives. The traditional approach of testing variations of known drugs is certainly not going to dive very deeply into this potential pool either, but at least it has the advantage of exploring compound space based on knowledge, so the search will be made more effectively.

Of course, our chances of encountering cross-resistance are enhanced if we limit ourselves to compounds similar to those currently in clinical use. Consequently, it would be most useful to find molecules that might lead to development of drugs with novel chemical scaffolds. These statements represent the basic premise of the so called fragment-based drug discovery approaches (FBDD).In principle, there are in principle several ways to construct novel ligands designed for a particular target that could subsequently become lead candidates. These entail a modest exploration of “drugable” molecular space, but the efficacy of this approach could be largely enhanced by using knowledge of the target. Sometimes that knowledge may be functional, but more often it is structural. That is, we presume the target protein (or nucleic acid) assumes a structure, and some aspect of that structure is used to search for small molecule ligands that might bind and be used to develop a drug candidate.

The idea is that small molecules with an inherently lower binding affinity would make better starting points for a chemistry program. Starting from a low molecular weight compound with optimum binding to the protein, chemical modifications that increase molecular weight can more easily be applied to optimize the drug profile of a compound.

The results show that FBDD is a powerful alternative approach for lead finding. Use of this approach is not always appropriate however. Studies have showed the potential of using small weak binders, an approach they term “Small is Beautiful”, to facilitate the drug discovery cycle. It is also identified that the need for a commitment to screen at high concentrations and the development of NMR screening libraries as two areas of development for successful fragment based drug design with a shorter iteration cycle. 

References: 

http://www.denovopharma.com/page2.asp?PageID=486

http://pt.wkhealth.com/pt/re/rdd/abstract.00126839-200809040-00002.htm;jsessionid=LDCchFQcgBhJHk4vPpZPhNklvT26RzCppxJQmTh93jnGLTMKFXG3!536197444!181195628!8091!-1 

http://www.ebi.ac.uk/Information/events/therapeutic/doc/Hajduk_TACBAC_2007.pdf 

http://www.postgenomicnmr.net/