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