Drug Designing: Open Access
Open Access

Expanding the scope of fragment screening libraries: Thinking in 3D

International Conference and Expo on Drug Discovery & Designing

August 11-13, 2015 Frankfurt, Germany

Angelo Pugliese

Posters-Accepted Abstracts: Drug Des

Abstract :

Fragment-based drug discovery (FBDD) methods are a proven strategy for hit identification, providing diverse, high quality start
points for numerous drug discovery programmes. Many fragment hits have been optimised and transitioned to the clinical setting
with one, namely Vemurafenib gaining FDA approval to treat late stage V600E mutant B-Raf driven malignant melanoma. Critical
for successful fragment screening is a high quality compound library. Whilst fragment screening techniques have evolved over the
years, increasing in sensitivity and throughput, fragment library molecules have received less attention. Many fragment libraries are
chemically diverse and have been selected based on a good balance of properties, however, they all tend to have limited 3-dimensional
diversity, typically being composed of flat sp2-rich aromatic and heteroaromatic compounds. This move towards “flatter” molecules
not only reduces the sampling of chemical space available for fragments but also fails to capitalise on the additional attributes of sp3
character. Recently, two groups have independently published data showing the improvements in profile and project progression by,
for example, increasing the proportion of sp3 centres contained in molecules or reducing lipohilicity. In addition, there are multiple
examples in the literature reporting the positive impact of increasing sp3ness or 3-dimensionality through inducing conformational
twist. This talk will discuss fragment library composition along with suggestions and practical examples of how future, more
structurally diverse fragments which occupy different regions of chemical space to the vast majority of current fragment libraries can
be designed and selected.