Lead Discovery

Pharmacopeia has effectively industrialized the synthesis of high quality combinatorial libraries and the extraction of information from them through biological screening. An essential component that enabled Pharmacopeia to do this is a proprietary chemical encoding/decoding process called ECLiPS® technology.

Polymer bead supported organic synthesis is the most efficient method for constructing large collections of related molecules. By performing chemistry on polymer beads, a single chemist can perform 1,000’s of reactions at a time, with no more effort than performing a single reaction.

Pharmacopeia employs a unique variant of this approach wherein each polymer bead not only contains the molecule being synthesized, but also a set of “tags” which are used to track and uniquely identify every molecule being synthesized.

For screening purposes, the drug-like compound is detached from the polymer support leaving the tags behind with the bead. The compounds are then evaluated in any standard biological screening operation. Once biological activity is seen, the tags that accompanied the active compound are cleaved from the polymer bead in a separate step and “read” (decoded) by gas chromatography. The resulting pattern of tags revealed by the gas chromatogram is analogous to a bar code that uniquely identifies the active compound. The power of this method is not just the ease of identifying an active compound from screening operations. A larger benefit accrues when many related compounds are screened and decoded because the data generated, by compiling multiple decodes, provide valuable structure-activity relationship (SAR) information that acclerates drug discovery.

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8 Million Member Compound Collection

As a consequence of the ability to synthesize large libraries of molecules, Pharmacopeia has been able to build what is, by a substantial margin, the world’s largest collection of discrete small molecules, with structures and properties designed for their drug-like characteristics and optimizability.

Currently, Pharmacopeia’s internal compound collection numbers 8 million compounds and represents a significant source of competitive advantage for the company. The collection is at least twice the size of even the largest Big Pharma collections.

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Ensuring Drug-Like Libraries

To ensure that the libraries we synthesize for screening contain “drug-like” compounds we utilize a proprietary computational tool called Library Profiler to plan and design synthesis of the libraries. Two key features of Library Profiler are rapid property calculation (properties for 100,000 compounds in less than a minute) and natural visualizations. These two features enable scientists to design a library through multiple iterations thereby ensuring that the library we ultimately synthesize is both drug-like and diverse. These features accelerate compound optimization.

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Focusing on Biologically Relevant Areas of Chemistry Space

One of the key realizations from the genome projects of the last decade is that the universe of proteins is dominated by a few key families: GPCRs, kinases, nuclear hormone receptors and proteases, as examples. With this in mind we have developed novel methods to design libraries for some of these major families that allow the incorporation of biologically relevant information prior to synthesis, while still allowing sufficient diversity not to constrain serendipitous discovery. These novel technologies include methods to dock and analyze millions of compounds in numerous x-ray structures and homology models to ensure that the compounds are complementary to the binding sites of interest prior to synthesis. A second novel method is the compression of molecular representations to one-dimension and subsequent alignment of multiple molecules with the same biological activity. These alignments highlight the conserved features of the bioactive molecules allowing the design of novel compounds with greatly improved likelihoods of having activity against that target, or alternatively, focus attention on potential concerns.

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Ultra-High-Throughput Screening Platform

We have built a highly efficient platform that enables the screening of over 5 million compounds in as little as 2 months. The platform utilizes a 1536-well format. We were the first organization to successfully implement screening on this scale and with this throughput, and our platform continues to be the most efficient and effective approach to screening our ECLiPS® libraries. The approach we take to screening is termed “statistical screening” and has numerous benefits when combined with our types of libraries as compared to screening conventional pharmaceutical libraries using standard industry approaches. These benefits include multiple starting points for lead optimization, massively reduced false-positive rates, and unparalleled richness of SAR data that contributes to an accelerated lead optimization program.

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Mining Screening Data

We have screened between 2 and 5 million compounds against approximately 150 targets—generating nearly 500 million biological data points. Using this data we have shown that several calculated molecular descriptors identify portions of chemical space that are significantly enriched with biologically active molecules. These results are the first such results based on experimental data. This knowledge is leveraged at Pharmacopeia in the design of new small molecules for screening.

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Elimination of False Positives

Due to the statistical nature of screening at Pharmacopeia, wasted effort from following up false positives is largely eliminated.

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