Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

Abstract

Most libraries for fragment-based drug discovery are restricted to 1,000–10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC β-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

“…58 In both, the ligand carboxylate participates in an ionic interaction with Arg288 and interactions that occur with many of the conserved aromatic residues in the UGM– 22 complex are observed in the docked model. Opposing conformations of the flexible loop (Figure S13), sequence differences between K. pneumoniae UGM and C. diphtheriae UGM distal to the binding site, and the small variation in the ligand ( 6 versus 22 ) itself may contribute to discrepancies between the poses.…”

“…64 Together, our data are consistent with the growing body of literature that suggests virtual screening and HTS are complementary. 37,58,65,66 …”

Docking Screens for Novel Ligands Conferring New Biology

“…51,52 With all their potential liabilities, fragment docking can fill chemotype holes in empirical libraries, sometimes leading to hits with much higher affinity and ligand efficiency than empirical screens alone. 174 The gap in our libraries for covalent probes is more compelling still. From bitter experience with false positives, most empirical screening libraries have been scrubbed clean of hot electrophiles, making it hard to intentionally screen a large library for covalent ligands.…”

Strategies to diversify natural products for drug discovery

“…Natural products are often perceived as chemically complex molecules with certain biological activity, offering particular fragments into ligand‐efficient and selective novel chemical entities . Screening these natural products and analogues with a multitude of three‐dimensional frameworks to determine their ability to bind to a protein target or modulate macromolecule‐perturbing properties supports modern drug discovery .…”