- About
- Research
- Research Overview
- Chemical Biology and Medicinal Chemistry
- Chemical Biology and Medicinal Chemistry Overview
- Discovering Enzyme Substrates and Functions
- Discovering Protein Ligands to Probe and Alter Function
- Discovering Enzyme Activators
- Analyzing Mechanisms of Drug Resistance via Chemical Biology
- Analyzing Enzyme Conformational Dynamics, Substrate Binding, and Catalysis
- Effective Drug Targeting of Pathogens via Medicinal Chemistry
- Computational Chemistry and Biology
- Computational Chemistry and Biology Overview
- Modeling protein regulation via allostery and post-translational modifications
- Visualizing and integrating bioinformatics and biomolecular data
- Modeling membrane permeation to optimize pharmacokinetics
- Determining enzyme function by predicting substrate specificity
- Physical Biology
- Protein and Cellular Engineering
- Protein and Cellular Engineering Overview
- Monitoring enzyme activity and disease biomarkers
- Generating human proteome antibodies via phage display and directed evolution
- Globally analyzing and dissecting apoptosis
- Proximity tagging of protein-protein interactions
- Investigating cellular interactions in tissues
- Creating fluorescent probes targeting the genome and key bio-pathways
- De novo design of catalytic and membrane proteins
- Probing and modulating membrane proteins
- Education
- People
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- Events
Accomplishments
Computers in molecular sciences and drug discovery
The Department of Pharmaceutical Chemistry has a long and storied history of developing computational technologies for visualization of protein structures and designing mathematical tools to predict protein structures and protein/small-molecule interactions.
2010s: Computational drug design: PLOP and SEA
Introduced new computational methods to accurately model proteins and complexes (Protein Local Optimization Program, PLOP) and to predict new drug activities via statistical analyses of chemical structures (Similarity Ensemble Approach, SEA).
Impact
These methods are allowing pharmaceutical researchers to model how existing drugs function, where else they might also be useful, and how to address the causes of their side effects.
Principal faculty
- Brian Shoichet, PhD (SEA; DOCK 3.5 derivatives)
- Matt Jacobson, PhD (PLOP)
- Michael Keiser, PhD (SEA)
2009–: Systems pharmacology
Helped define the new field of quantitative systems pharmacology, which models drug activity across multiple biological scales.
Impact
New tools and methods are being used across academia and industry to understand and predict drug activity, side effects, transport, clearance, and pathways.
Principal faculty
- Michael Keiser, PhD
- Brian Shoichet, PhD
- Kathy Giacomini, PhD (Department of Bioengineering and Therapeutic Sciences)
1980s–1990s: Protein folding pathways
Pioneered theory of protein-folding pathways as funnels within a free-energy landscape.
Impact
Introduced fundamental biophysical and statistical concepts currently used in mathematical models of protein folding.
Principal faculty
- Ken Dill, PhD
1980s: Computational drug design: DOCK and AMBER
Invented the first applications of computers to investigate questions in pharmaceutical chemistry, allowing researchers to calculate, display, and analyze molecules in three dimensions. Notable early accomplishments were the invention of software for computing protein structures (Assisted Model Building with Energy Refinement, AMBER) and for automatically docking drug molecules into their target receptors (DOCK).
Impact
Computer-based approaches speed drug development by more efficiently sorting out or screening from millions—even billions—of chemicals those compounds that have the best potential for drug development.
Principal faculty
- Irwin “Tack” Kuntz, PhD (DOCK)
- Peter Kollman, PhD (AMBER)
1970: Resource for Biocomputing, Visualization, and Informatics (RBVI)
Established in 1970, the RBVI pioneered the use of computational visualization to help answer questions about biological and pharmaceutical structure and function.
Impact
The tools and technologies developed in the RBVI—such as Chimera and Cytoscape—are used worldwide to visualize and organize biological information from the atomic to the supramolecular levels.
Principal faculty
- Robert Langridge, PhD
- Thomas Ferrin, PhD
Drug discovery and chemical biology
The Department of Pharmaceutical Chemistry has been a pioneer in developing new approaches, chemical tools, and leads for drug discovery for challenging and high-value targets.
2007: Infectious diseases
Pioneered identification and exploitation of therapeutic targets for infectious diseases.
Impact
Department investigators have been instrumental to the success of the HARC Center (HIV Accessory and Regulatory Complexes: A Collaborative Research Center at UCSF and UC Berkeley), whose mission is to develop a structure-based understanding of host-HIV interactions.
Principal faculty
- Charles S. Craik, PhD
- John Gross, PhD
- Matt Jacobson, PhD
2005–: Protein homeostasis
Advanced scientific understanding of how imbalances in protein homeostasis contribute to a wide range of disorders, including Alzheimer’s disease.
Impact
Healthy tissues maintain a delicate balance of protein homeostasis, in which protein folding and turnover are tightly regulated. In many diseases, proteins adopt pathological conformations to avoid normal protein quality control. Work by Jason Gestwicki, PhD and team has illuminated how proteins’ misfolding and protective factors—such as molecular chaperones—operate to counteract this process.
Principal faculty
- Jason Gestwicki, PhD
2000–: Expanding the “druggable genome”
Created chemical screening and informatics approaches to identify sites and compounds for targets that have been considered undruggable, and for which there are no adequate chemical starting points to initiate the drug discovery process, including protein-protein interfaces and allosteric sites.
Impact
Tremendous progress has been made to approach challenging targets formerly considered undruggable. Focusing on prediction of allosteric sites, investigators will find new ways to turn proteins off or on. Projects include: inhibitors of caspases (Michelle Arkin, Adam Renslo, and James Wells), disruption of protein dimerization (Charles S. Craik), and inhibitors of protein-protein interactions (Michelle Arkin, Jason Gestwicki, Adam Renslo, and James Wells).
Principal faculty
- Michelle Arkin, PhD
- Charles S. Craik, PhD
- William DeGrado, PhD
- Jason Gestwicki, PhD
- Matt Jacobson, PhD
- Andrej Sali, PhD (Department of Bioengineering and Therapeutic Sciences)
- Brian Shoichet, PhD
- James Wells, PhD
1999–: Fragment-based lead discovery
Originated and popularized technologies for site-directed fragment discovery.
Impact
One problem with undruggable targets is finding the first small-molecule starting point. Fragment-based lead discovery breaks the problem into smaller pieces by testing compounds that are roughly half the size of a typical drug lead. Small compounds with low complexity bind to subsites within a drug-binding site, allowing the researcher to get a foothold. The disulfide trapping method known as Tethering is a site-directed method in which a native or engineered cysteine residue on the protein captures thiol-containing fragments. Tethering—originally developed by James Wells, PhD, and colleagues at Sunesis Pharmaceuticals—has been further advanced at UCSF after Wells joined the Department of Pharmaceutical Chemistry faculty. UCSF investigators have discovered new allosteric sites with Tethering, and tethered compounds have acted as molecular chaperones for crystallography.
Principal faculty
- Michelle Arkin, PhD
- Matt Jacobson, PhD
- Adam Renslo, PhD
- Brian Shoichet, PhD
- Jim Wells, PhD
1989–: Drug discovery for parasitic diseases
Identified a protease target needed by the parasite Trypanosoma cruzi, the etiological agent of Chagas disease, and determined the structure of the protein-identified inhibitors. Developed several high-throughput, whole-organism assays for parasitic diseases and discovered new drug leads for major neglected diseases, including Giardia, Amoebiasis, Chagas disease, Leishmaniasis, and Schistosomiasis.
Impact
One billion people around the world are at risk for contracting parasitic diseases, with the greatest impacts in the poorest populations. School scientists have developed high-throughput screens to identify new compounds that may be used as drugs to treat these diseases. The assays themselves have led to innovations in microscopy-based screening for live organisms, including quantifying movement in a high-throughput format. Drug leads are being developed for Schistosomiasis (200 million people infected), Chagas disease (10 million people infected), and Amoebiasis.
Principal faculty
- Michelle Arkin, PhD
- Charles S. Craik, PhD
- Robert Fletterick, PhD (Department of Biochemistry and Biophysics)
- James McKerrow, MD, PhD
- Adam Renslo, PhD
- Jack Taunton, PhD (Department of Cellular and Molecular Pharmacology)
1983–: Molecular parasitology
Linked the purine salvage enzymes in Giardia and Trichomonas to cell cycle regulation in African trypanosomes to help identify protein targets needed by the parasite for survival.
Impact
Protozoans are a major cause of deadly and debilitating illness of humans and livestock throughout the world. School scientists established the basis for molecular parasitology that is commonly used today to produce effective species-specific molecules of medicinal importance.
Principal faculty
- Ching Chung “C. C.” Wang, PhD and Alice L. Wang, PhD
1983–: Viral proteases
Identified a small molecule inhibitor, as well as a "defective version" of HIV protease, that blocked the ability of the virus to process viral proteins, thereby preventing HIV from accomplishing disease-related tasks in the body.
Impact
Pioneering work led to the appreciation of HIV protease and other proteases as excellent drug candidates, thereby contributing to the development of marketed antiviral drugs.
Principal faculty
- Charles S. Craik, PhD
- Paul Ortiz de Montellano, PhD
- Irwin “Tack” Kuntz, PhD
1980s–: Cytochrome P450s and drug metabolism
Revealed an advanced understanding of mechanism-based inhibition of cytochrome P450 enzymes and established its utility in both drug design and the avoidance of drug structures with undesirable P450 inactivation liabilities.
Impact
Because of this work, current drug design avoids substructures that cause cytochrome P450 inactivation, except for some agents for which a P450 enzyme is the drug’s specific target.
Principal faculty
- Paul Ortiz de Montellano, PhD
Engineering proteins and cells to affect biology
Department of Pharmaceutical Chemistry investigators have developed breakthrough technologies in protein and cellular engineering, leading to the development of engineered proteins to control signaling, high-throughput discovery of recombinant antibodies, and engineering of synthetic tissues.
2012: Global landscape of HIV human-protein complexes
Discovered and validated new human HIV protein interactions essential for viral replication and infectivity.
Impact
Knowing the “parts list” for HIV-human complexes allowed reconstitution of key events in the HIV viral life cycle. This research paved the way for structure determination of critical but recalcitrant HIV-host complexes which can be utilized for next-generation antiretroviral drug discovery that is less prone to resistance.
Principal faculty
- Al Burlingame, PhD
- Nevan Krogan, PhD (Department of Cellular and Molecular Pharmacology)
2003–: Recombinant, renewable antibodies for conformational states of proteins
Using the technology of bacteriophage display, engineered antibodies have been identified that recognize key conformational states of proteins and, in particular, enzymes.
Impact
Providing valuable reagents for non-invasive imaging of cancer cells for stratification of patient populations, monitoring drug therapy, and identifying targets for therapeutic intervention. Proteins are constantly fluctuating among their different conformational states in the same way that a person does not stay fixed in one position throughout the day. Using recombinant antibodies to trap the different states of these proteins provides insight into the functional states of the proteins and the cells that produce them.
Principal faculty
- James Wells, PhD
- Charles S. Craik, PhD
1990–: Protein engineering to understand and modulate signaling pathways
Developed new protein-engineered tools to probe signaling pathways involved in proteolysis, ubiquitination, phosphorylation, and cellular trafficking.
Impact
Understanding how information flows into and out of cells through signaling pathways is fundamental to modulating disease. Such signaling pathways are complex, involving multiple components and compartmentalization. These new tools are helping us to dissect these pathways and to identify key nodes for therapeutic intervention.
Principal faculty
- Charles S. Craik, PhD
- Xiaokun Shu, PhD
- James Wells, PhD
Development of physical methods in biology
2007–: Development of high-resolution microscopy for understanding cell biology
Leading development of tools such as STORM (Stochastic Optical Reconstruction Microscopy) for understanding dynamic cellular structures ranging from the cytoskeleton to chromatin.
Impact
The molecular architecture of cells is constantly being remodeled to reflect cellular states and transitions during movement and differentiation. We have developed super high-resolution imaging methods to watch these events in cells.
Principal faculty
- Bo Huang, PhD
- Xiaokun Shu, PhD
1990s–: Structure determination of proteins involved in disease
Applied sophisticated nuclear magnetic resonance (NMR) techniques to describe important protein structures in HIV-AIDS, influenza (M2 protein), Kaposi’s sarcoma-associated herpesvirus, protease, and fatal neurodegenerative diseases such as bovine spongiform encephalopathy (mad cow disease) which can serve as targets for the rational design of potential new and effective drugs. Based on this knowledge, department scientists designed anti-influenza compounds that address problems associated with drug resistance.
Impact
The power of NMR and other techniques to see the architecture of molecules involved in disease makes it easier to determine how to rationally design drugs that bind to, or incapacitate, those molecules.
Principal faculty
- John Gross, PhD
- Thomas James, PhD
- William DeGrado, PhD
- Charles S. Craik, PhD
1970–: Development of mass spectrometry and proteomics for biology
Pioneered the development of high-resolution mass spectrometers for sensitive detection of biomolecules in complex biological samples.
Impact
The field of modern day proteomics is largely dependent on high-resolution mass spectrometry, which has been a major focus in the department.
Principal faculty
- Al Burlingame, PhD