Fragment-based Drug Discovery
Fragment-based drug discovery is gaining increased attention as a method of generating lead-like compounds for biological targets such as enzymes in addition to difficult targets (protein-protein interactions). However, establishing the technology requires expert experience and expensive instrumentation. Therefore, some companies choose to outsource.
Evotec (www.evotec.com) established an Innovation Centre for fragment-based drug discovery that utilizes its EVOlution technology to identify novel small molecule fragments for biological targets and to rapidly optimize the fragments to subsequent lead compounds and development candidates.
Mark Whittaker, Ph.D., senior vp of drug discovery says, “Fragment-based drug discovery offers an important alternative approach that allows identification of novel small molecule fragments for many biological targets, especially those that may have been challenges using traditional drug discovery methods.”
The fragments, which are low molecular weight counterparts (~150–350 daltons) of small molecules (~500 daltons), bind with low affinity to a biological target. “They are important starting points for drug discovery, yet can prove difficult to identify due to their weak interactions with protein targets. That is where our EVOlution technology is critical. This technology allows us to identify extremely weak interactions between a protein target and a fragment; much weaker than can be detected using traditional methods. In addition to being highly sensitive, our approach is also high throughput and allows us to test thousands of fragments in a very short space of time.”
Dr. Whittaker notes that Evotec routinely tests its library of 20,000 fragments against protein targets. X-Ray crystallography studies are then conducted by Evotec to determine how fragment molecules interact with the target protein. This forms the basis of their structure-based optimization of the fragments into lead compounds.
According to Dr. Whittaker, Evotec has validated the technology against biologically relevant targets such as kinases, proteases, and protein-protein interactions related to the central nervous system, oncology, inflammation, metabolic diseases, and cardiovascular diseases. Evotec is currently building a pipeline of programs for early partnering with pharmaceutical and biotechnology companies in addition to discussing using the technology to identify clinical candidates for their partners’ protein targets.