Why we Perform Internal Research
We perform internal discover to further develop and test our technologies on projects of interest to us. While we often collaborate with academics, institutes, and biotechnology or pharmaceutical companies on their targets, by taking on targets in-house we can use beta versions of our technologies and hone them as we go through discovery. The next paragraph introduces the motivating observations that have driven and continue to drive our development. This is followed by an example where we applied the technologies to an interesting “superfamily” of proteins, the GHKL family, that perform different biological tasks but possess sufficiently similar active sites so one can develop new chemical entities to target several at the same time. This is of interest in infectious disease. After our own initial development this was funded by an NIH grant and formed the basis of a collaboration with Stanford Research Institute (SRI) to further develop our lead compounds. We currently have funding from a foundation grant to allow us to develop initial leads to target a muscular skeletal disease in collaboration with an academic laboratory.
Our Gestalt on Structure-Based Discovery
Current early drug discovery is driven by high-throughput screening of compound libraries, aided by computational analysis of a target and/or lead compounds. Biopredict, Inc. have developed a suite of computational methods to address these problems that:
Our approach makes use not only of available information on a specific target of interest, but also of information on related targets within the target protein family. We have honed our current approach through collaborations with biotech and pharmaceutical companies to identify lead compounds, to increase their potency, to increase specificity in target families, and to design family-focused combinatorial libraries. Targets have included nuclear receptors, protein kinases and phosphatases, nucleotide synthases, and serine and other proteases as as well as other more novel targets.
An advantage of our family based multi-protein-target approach is that, at the first stage of hits elucidation and structural hypothesis verification, we screen for ligands that bind to a conserved structural motif common to this family of proteins. We use a complementary approach that detects activities against multiple members of the family, helping to prove our structural binding mode hypotheses.
Advantages of our approach over other structure-based virtual screening methods
Many scoring functions used to dock and evaluate docked compounds are still imperfect and will probably remain so for quite some time. As a result, the highest scoring compound is not always active, and the highest scoring conformation of an active compound is not always predicted correctly. Our information-driven approach circumvents this problem by augmenting energy scores using hypothesis-driven methods to select compounds that exhibit similar binding modes to those already established either against the specific target or against homologous targets. When used to select compounds these methods postulate that if compounds possess similar modes of binding to known actives they will themselves be active. It has been our experience that the application of these methods when directly compared to selection of compounds by docking scores alone results in a roughly ten-fold enrichment in identified actives for a screen. Despite this enrichment, we generally include up to ~1000 compounds in our first screen selected using multiple hypotheses to increase the number of hits obtained. A further improvement is the inclusion of a multiply iterated screen. Once hits are found, testing purchasable compounds related to identified hits is an attractive, efficient, and inexpensive way to expand the number of hits considered within a given lead series before committing to chemical synthesis. A final and perhaps defining advantage of our methods is that they work with multiple related targets at the same time. Careful analysis of active site similarities for multiple targets enables the identification of common focused libraries for testing. If active site similarities are great enough, the same methods can lead to multiple-target inhibitors. A compound that hits more than one target in a sensitive pathway has a higher likelihood of avoiding drug-resistant mutations when targeting infectious disease organisms (we are pursuing this approach in kinases with a client company).
The GHKL Protein Superfamily
The GHKL superfamily includes diverse protein families as DNA topoisomerase II, molecular chaperone Hsp90, DNA-mismatch-repair enzymes MutL, and histidine kinases. The superfamily is rich in established and proposed drug targets, for both cancer and bacterial infectious disease. We have developed new technologies to implement a structure-based, computationally-driven approach to identify novel compounds and to design combinatorial chemistry libraries that are active against multiple members of the superfamily. Our goals remain to generate high affinity, specific inhibitors for several GHKL targets, with supporting broad-spectrum libraries active against multiple GHKL targets to establish a superfamily-based SAR. Work has been funded by NIH grants, and through collaboration with SRI.