Informatics of docking libraries & docking screens

Bio-likeness of purchasable chemical space
Figure 1. Purchasable chemical space is >> 1000-fold more bio-like than possible chemical space. The GDB is a calculated library (Fink & Reymond, 2005) of the 27 Million possible stable molecules composed of C, N, O, F and H atoms, up to 11 atoms in size. The purchasable GDB is the subset that can be purchased. Both sets are compared to a. metabolites and b. natural products. From Hert, 2009.
AmpC inhibitor by NMR AmpC inhibitor by fragments
Figure 2. Left A ~5 mM AmpC inhibitor found by an NMR fragment screen. Right A 0.2 mM AmpC inhibitor found by fragment docking (yellow x-ray, green docking). The TINS fragment bound in a site unsampled by docking.

Comparing the potential size of chemical space to the actual size of screening libraries (Hann, 2001), it is a miracle that screening ever works. One reason why it does, we have argued (Hert, 2009; Figure 1), is that the libraries that are actually screened are fortuitously biased towards bio-relevant chemotypes. The chemical content of our libraries, either for high-throughput, fragment, DNA-encoded, or docking screens, is as important for the success of a discovery campaign as is the quality of our assays and the quality of our scoring functions.

An active project in the lab is to understand how to enrich libraries with bio-relevant molecules, and with such molecules grow the libraries. We have investigated how docking compares to high-throughput screens (HTS) against targets such as PTP-1B, AmpC, β-lactamase, and Cruzain, and how docking fragments compares to docking larger, lead-like molecules, again using AmpC and TEM-1 as model systems. A very recent direction involves efforts to grow our docking libraries by log orders. Already, at 3 to 6 million molecules, docking screens are larger than most HTS campaigns; over the next several years we expect the docking libraries to expand by 1000-fold, introducing fascinating new challenges and huge opportunities.

A close coupling between theory, docking, and experimental testing is central to the enterprise. Key papers include:

Supported by NIGMS GM59957 & GM71896.