In what we hope is a new series bringing the latest in Fragment Science up for discussion, we present today to you a discussion of Infarmatik's In-3D Library. We look forward to this discussion, and hopefully, many more.
Fragment based drug discovery has been shown to provide a rapid means for transforming low affinity “hits” to optimized leads. However, most currently available fragment libraries are limited in usefulness, mainly because over 90% of the molecules are planar and thus do not fit well into 3-dimensional receptor protein binding sites. InFarmatik realized [Ed: and others] that “real 3-D” structures offer a better fit within the uneven binding surfaces of protein hot-spots (business sites) than do planar compounds. To address this issue, we have developed a specific series of novel and diverse 3-D fragments, which are not available from any other commercial sources. The structure types of the first release contain 2,3, and 4 member non-aromatic ring systems, with various attachment points, including spiro and 1,2 anellation, 10 electron systems connected to saturated ring systems, saturated bis-heterocyclics and rod shaped compounds. We believe these compounds will exhibit the ability to bind to a wide array of protein targets. In addition, we can offer another 435 structures from existing stock, which conform to Ro3 and are quite “fragment-like”.
Most of the compounds have soft scaffold structures: meaning they were designed to have low reactivity centers to avoid non-specific binding, while preserving the ease of chemically coupling them to each other or to other fragments. The attachment points in the molecules in many cases are useful for regiospecific reactions.
Here are the relevant properties of the 3-D fragment library:
Size: 119 3-D Fragments
Average MW=230 Da
average logP value (calculated) =1.88
confirmed minimum water solubility of at least 0.1% in 2% aqueous DMSO.
Solubility data available for all compounds
Highly diverse, as shown by 3-D Diversity Analysis using ChemAxon supplied tools
Here are the relevant properties of the new standard fragment set
· Size: 435 Fragments
· Average MW=237.8 Da
· Average LogP value (calculated) =2.27