Protease enzymes of the Kaposi’s sarcoma-associated herpesvirus (KSHV Pr) require two monomer proteins to combine into a dimer in order to activate. Dotted black box is the protein-protein interface targeted for disruption by Craik Lab researchers. (Colored balls represent amino acids—methionines—labeled to help determine if screened fragments inhibit dimerization.)
To discover new drugs and chemical probes, researchers have traditionally screened small molecules—small enough by weight to pass through cell membranes.
Sepsis occurs when the body responds to an infection with a mix of tissue-damaging inflammation and anti-inflammatory responses. This biological storm can lead to acute organ dysfunction (severe sepsis) and dropping blood pressure that does not respond to intravenous fluids (septic shock).
In these multiple images of P. aeruginosa biofilm a bacterial community that takes the form of mushroom-like structures. The main, upper left image looks down at the biofilm, the lower, right-hand images show cross-sections. This biofilm was cultured from the airways of a patient with cystic fibrosis.
Nearly every human bacterial infection—including some of the most serious, life threatening, and costly to treat—can take the form of a biofilm, in which bacteria aggregate into structured communities that enclose themselves within a secreted slime.
Spiked rods of uric acid crystals from synovial fluid photographed under a microscope with polarized light. In patients with gout, such crystals can accumulate in the joints, causing pain and inflammation.
Allopurinol, the first-choice medication for treating gout—an excruciatingly painful condition that is the most common form of inflammatory arthritis, afflicts more than eight million Americans, and is on the rise worldwide—is not fully effective in more than half of patients.
About 10 to 20 percent of women suffer from new-onset depression during pregnancy or after giving birth. Untreated, the impact of such illness can be profound, ranging from substance abuse, poor prenatal care, and miscarriages to impaired infant bonding and developmental delays.
It can take just the flick of a genetic switch for breast cells to kick-start the normally well-regulated process of growth seen in puberty, pregnancy, or the menstrual cycle—or the mutation of that switch to initiate the unchecked proliferation of cancer.
Every year U.S. drug regulators approve dozens of new medicines as “safe and effective,” but just how effective are they? How well do they alleviate specific aspects of illness, whether light sensitivity from migraine headaches or itching from eczema?
A schematic diagram of the mechanisms built into each cell in the in silico hepatocyte cultures. Checkmarks indicate events affected by the physical and chemical properties of a specific virtual drug object. For example, depending on such properties a given drug bound to an enzyme can have a different probability of being metabolized or released. (Source: Drug Metab Dispos. 2011 Oct;39(10):p. 1910-20)
A holy grail of drug discovery is to answer key questions about potential new drugs less by experiments in petri dishes and lab animals and more by faster, cheaper engineering efforts using predictive computer models.
UCSF scientists are studying key drug transporters that play roles in drug absorption and elimination. Shown here: OCT2 and others in the membrane of cells in the kidney tubules (at right). The urine collecting tubules interface with capillaries (at left) to remove substances such as medications and environmental toxins from the blood.
To reduce the risk of toxic drug interactions, UCSF's Kathy Giacomini, PhD, and colleagues are screening thousands of prescription drugs, testing how much they inhibit key proteins in kidney and liver cell