Lokey Research Group

Our Mission in Science

Our mission is to create a new drug discovery paradigm that lies at the interface between conventional small molecules and biologics (e.g. antibodies and recombinant proteins). The drug discovery community has traditionally shied away from molecules in this size range (between ~500 and 10000 Da) because of the long-held perception that compounds with molecular weights much beyond 500 cannot cross cell membranes and therefore can’t be made orally bioavailable, that is, made into a pill. Further, molecules with low cell permeability are, by definition, incapable of acting on targets within the cell, limiting such molecules, including biologics, to injectable drugs against extracellular targets.

Modern “-omics” technologies such as shRNA, expression profiling, deep sequencing, and proteomics, have delivered vast datasets that biologists are beginning to mine for clues into the molecular basis of disease. As a result of these efforts, a wave of new candidate drug targets has emerged. Unlike typical enzymes and receptors, many of these new targets are signaling proteins and transcription factors whose functions are carried out through protein-protein or protein-DNA interactions. Since few of these biomolecules have conventional small molecule binding sites, finding cell permeable drugs that can modulate their functions presents one of the major challenges in drug discovery going forward. Medicinal chemists are now charged with the task of identifying molecular scaffolds that are large and complex enough to bind macromolecular interfaces, but yet have the membrane permeability associated with typical small molecule drugs.

Our laboratory studies membrane permeability in molecules whose structures violate classical predictors of “drug-likeness” (e.g. Lipinski’s “rule of five”) based on molecular weight and polarity. Many of these ”rule breakers” are natural products such as the cyclic peptide cyclosporine A (CSA), a highly effective immunosuppressive drug that is orally bioavailable despite its molecular weight of ~1200. We are investigating the physico-chemical properties of molecules like CSA and, using synthetic model systems, are uncovering interesting relationships between structure, conformation, and membrane permeability in these molecules.

Another major focus of the laboratory is the development of new methodologies for synthesizing “natural product-like” cyclic peptides.  In collaboration with Prof. Matthew Jacobson at UCSF, we have developed robust computational methods for predicting membrane permeability in large cyclic peptides. Using a combination of synthetic and computational approaches, we are preparing large libraries of cyclic peptides whose structures are biased toward membrane permeability. We are screening these libraries in the UCSC Chemical Screening Center in a variety of phenotypic assays, from antimicrobial screens to image-based screens in human cancer cell lines, with the ultimate aim of identifying cell-permeable cyclic peptides with potent biological activities in multiple defined cell-based and in vitro systems.

See Our Current and Published Research Projects