New Fragment Library to Enhance Structure-Based Drug Design

Thermo Fisher Scientific introduces the latest addition to its Maybridge Fragment Range, the Maybridge Ro3 Diversity Fragment Library. This offers both an improved structural diversity profile and experimental solubility data for every one of the 1,500 member compounds.

The new library from Thermo Fisher Scientific has been computationally engineered to build on the key customer-driven features of the original Maybridge Ro3 Library, such as “Rule of Three” (Ro3) compliance, pharmacophoric enrichment and quality assurance of at least 95 percent. Full Ro3 compliance means that all 1,500 fragments have the physicochemical properties that increase the probability of successful “hits.” The broad portfolio also provides access to analogues for fragment hopping, as well as reactive analogues for rapid hit evolution and derivatisation. Consequently, these Maybridge Fragments provide an ideal starting point for a lead-optimisation, structure-based drug discovery programme and the ultimate evolution of a new molecule in the drug discovery process.

Every fragment in the new Maybridge library has been experimentally triaged to assure solubility in both DMSO (200mM) and aqueous phosphate buffer (1mM). Aqueous solubility is a prerequisite for successful in vitro testing, as poor solubility can compromise the robustness of the screening data through aggregation and promiscuous inhibition. Fragment hits with poor aqueous solubility are also more likely to produce evolved analogues with inferior ADME properties, such as plasma protein binding, poor systemic distribution and an increased likelihood of candidate attrition. The Maybridge Ro3 Diversity Fragment Library mitigates all such issues.

When building the new Maybridge library, Maybridge scientists applied Daylight-based structural fingerprinting techniques (1024 bit length) to an Ro3 compliant set of 8,000 fragments and the fingerprinted set then clustered using industry standard clustering software (DBClus)1. The resulting representative set of 1,500 high-quality molecules consists of 819 cluster centroids and 690 singletons at a Tanimoto level of 0.66.

“As the field of fragment–based drug discovery continues to mature there is an increasing need to gain access to fragments of the highest quality,” said Simon Pearce, Maybridge product manager. “Built on a pedigree of almost 50 years of heterocycle research, our Maybridge Fragment Range has grown with the technology over the past six years, as structure-based techniques such as NMR become more central to the drug discovery process. In fact, many successful fragment screening programmes have Maybridge Fragments at their heart.”