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Chemistry and Biochemistry
University of California
230 Physical Sciences Bldg.
Santa Cruz, CA 95064
Phone: (831) 459-4002
Fax: (831) 459-2935
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Scott Lokey Assistant Professor of Chemistry Ph.D., University of Texas, Austin Office: 352 PSB Phone: (831) 459-1307 Fax: (831) 459-2935 lokey@chemistry.ucsc.edu

Lokey Research Group Department of Chemistry University of California 1156 High Street Santa Cruz, CA 95064 Office Hours Class Times & Locations Labs: 365 PSB, 9-2978 Lokey Research Group

RESEARCH INTERESTS: Bioorganic Chemistry, Cyclic Peptides, Cell Cycle and Signaling

Our research focuses on the discovery of chemicals that target and modulate cellular processes. We implement a variety of techniques, from organic synthesis to cell biology, and approach the discovery process from multiple angles. High-throughput screening techniques have allowed us to identify compounds that target cell cycle checkpoints in mammalian cells and yeast, and modern chemical genomics methods provide candidate targets for in vitro validation. We are also developing tagged versions of complex molecules such as cyclic peptides, in order to determine their molecular targets in the cell.

We’re also interested in unlocking the secrets of drug bioavailabiltiy, that is, the absorption of drugs across biological barriers into targeted tissues. The absorption of drugs is still an unsolved mystery in drug development, and current models are generally ineffective at predicting which drug candidates will be readily absorbed into the bloodstream and which drugs will not. Some molecular properties, such as hydrophobicity and molecular weight, correlate with bioavailability, although current models can account for only general trends. We have been using cyclic peptides as vehicles to test hypotheses connecting membrane transport to drug conformation, leading us to a deeper understanding of drug absorption across multiple structural types. In one study, we found that cyclic peptide stereoisomers can have vastly different passive membrane diffusion rates, which we attributed to differences in internally hydrogen bonded conformations. In other studies, we are focusing on modifications in the cyclic peptide backbone to enhance permeability. With a deeper understanding of the subtle structural factors that govern membrane permeability, we may begin to target processes inside the cell with compounds of increasing complexity and selectivity. Our long term goal in this area is to understand the principles that govern passive membrane permeability and use those principles to enhance the drug discovery process.

We are in the process of creating the UCSC Small Molecule Screening Center, and NIH-funded resource that will allow Santa Cruz researchers to screen tens of thousands of compounds a day in a variety of biological assays. Stay tuned for the UCSC Small Molecule Screening Center website, which is currently under construction. The opening date for the center is set for September, 2007.

SELECTED PUBLICATIONS

Nehil MT, Tamble CM, Combs DJ, Kellogg DR, Lokey RS. Uncovering genetic relationships using small molecules that selectively target yeast cell cycle mutants. Chem. Biol. Drug Des. 2007, 69, 258-264.

Schuresko LA, Lokey RS. A Practical Solid Phase Synthesis of Glu7-Phalloidin and Entry into Fluorescent F-Actin Binding Reagents. Angew. Chem. Int. Ed. 2007, 46, 3547-3549.

Combs DJ, Lokey RS; Extended peptoids: a new class of oligomers based on aromatic building blocks. Tet. Lett. 2007, 48, 2679-82.

Gassner NC, Tamble CM, Bock JE, Cotton M, White KN, Tenney K, St.Onge RP, Proctor MJ, Giaever G, Davis RW, Crews, P, Holman TR, Lokey RS; Accelerating the Discovery of Biologically Active Small Molecules Using a High-Throughput Yeast Halo Assay. J. Nat. Prod. 2007;

Ralifo P, Sanchez L, Gassner NC, Tenney K, Lokey RS, Holman TR, Valeriote FA, Crews P; Pyrroloacridine Alkaloids from Plakortis quasiamphiaster: Structures and Bioactivity. J. Nat. Prod. 2007 70, 95-99

Rezai, T, Bock, JE, Vuong, Kalyanaraman K, C, Lokey RS*, Jacobson MP*. Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability: Successful In Silico Prediction of the Relative Permeabilities of Cyclic Peptides. J. Am. Chem. Soc. 2006; 128, 14073-14080 (*Corresponding authors).

Rezai T, Yu B, Millhauser GL, Jacobson MP, Lokey RS. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J. Am. Chem. Soc. 2006; 128, 2510-2511.

Perlman ZE, Bock JE, Peterson JR, Lokey RS. Geometric Diversity Through Permutation of Backbone Configuration in Cyclic Peptide Libraries. Bioorg. Med. Chem. Lett. 2005; 15, 5329-5334.

Simon RA, Schuresko L, Dendurkuri N, Goers E, Murphy B, Lokey RS. One-bead-one-compound library of end-capped dipeptides and deconvolution by microflow NMR. J. Combi. Chem. 2005, 7, 697-702.

Lokey, R.S. “Forward chemical genetics: progress and obstacles on the path to a new pharmacopoeia.” Curr. Op. Chem. Biol. 2003, 7, 91-96.