SCIENCE & TECHNOLOGY INSULIN AND RECEPTOR Kotra and coworkers analyzed molecular motions and interactions between insulin and its receptor to design insulin mimics. Model shows interaction of a tyrosine residue (purple) in insulin (brown) with a hydrophobic pocket (orange) on the insulin receptor (green).
DRUGS BY DESIGN With little fanfare, structure-based drug design is filling development pipelines STU BORMAN, C&EN WASHINGTON
S
OME 15 YEARS OR SO AGO, BEFORE
combinatorial chemistry stole its limelight, structure-based drug design got lots of attention. Its now lower profile notwithstanding, structure-based design "is being used effectively in drug discovery, and progress continues to be made in both the methods and their applications," Charles H. Reynolds, group leader of computer-aided drug discovery at Johnson & Johnson Pharmaceutical Research & Development (f&JPRD), Spring House, Pa, said last month. Reynolds spoke in Philadelphia at the ACS Prospectives meeting "Advances in Structure-Based Drug Discovery," which he coorganized with chemistry professor Kenneth (Kennie) M. Merz Jr. of the University of Florida, Gainesville, and professor of
chemistry and biochemistry Dagmar Ringe of Brandeis University, Waltham, Mass. In structure-based drug design, the three-dimensional structures of bioactive agents and their targets are the basis of drug discovery. In the past few years, dozens of drugs discovered this way at least in part have reached the market or late-stage clinical trials, and research in the area continues to grow, Reynolds noted. Those approved drugs include the AIDS medications Crixivan and Viracept, the flu drug Tamiflu, the leukemia therapy Gleevec, and the cancer agent Tarceva. Success breeds success. Structure-based design continues to fill drug development pipelines and to play a key role in develop-
ing leads and improving drug properties. Nuclear magnetic resonance spectroscopy is a key source of 3-D information. At Utrecht University, in the Netherlands, researchers are using N M R data to help develop a lantibiotic-based alternative to vancomycin, the last-resort treatment of antibiotic-resistant infections. Lantibiotics are antibiotics containing the amino acid lanthionine. They kill bacteria by binding to lipid II, an essential component of bacterial cell wall biosynthesis, thereby causing pores to form in bacterial membranes. An N M R structure obtained last year by Eefjan Breukink, Robert Kaptein, and coworkers revealed that the lantibiotic nisin binds in an unprecedented manner to a pyrophosphate on lipid II. Vancomycin also binds lipid II, but bacteria can modify its binding site, and the change gives rise to bacterial resistance to the drug. On the other hand, no bacteria have yet been shown to develop resistance by modifying the lipid II pyrophosphate to which nisin binds. The researchers hope to generate nisin analogs for clinical testing in collaboration with an industrial partner. At Abbott Laboratories, Abbott Park, 111., meanwhile, associate research investigator Chaohong Sun and colleagues reANTI-AIDS AGENT Arnold and coworkers, in collaboration with groups from two companies, used X-ray crystallography to guide the design of diarylpyrimidine reverse transcriptase inhibitors such as this compound, TMC278 rilpivirine), for which a Phase II trial is currently being organized. cently used N M R to discover agents that target X-linked inhibitor of apoptosis protein (XIAP), an anticancer target. Using
The number of protein structures that have been determined is "on a steep climb, so there are a lot more targets available to do modeling around/' 28
C&EN
/
NOVEMBER
28,
2005
WWW.CEN-0NLINE.ORG
N M R structures they obtained of XIAP with and without Smac, a protein ligand, they designed nonpeptide Smac mimics. Among them, one binds XI AP nearly two orders of magnitude more strongly than Smac does.
munodeficiency virus (HIV) reverse tran scriptase in complexes with various antiviral drugs. On the basis of these structures, they discovered diarylpyrimidines that inhibit re verse transcriptase. These are now being de veloped as potential AIDS treat-
METABOLIZER The Astex group has determined several X-ray crystal structures of human cytochrome P45Q enzymes, including this one of CYP 3A4 complexed with an inhibitor (metyrapone). Another key source of 3-D information is X-ray crystallography. For example, re searchers at Rib-X Pharmaceuticals, New Haven, Conn., use X-ray crystallography to develop antibiotics that target the ribosome. From solving more than 115 anti biotic-bound ribosome X-ray structures, they have identified promising targets in the ribosome's 50S subunit. TO FIND compounds likely to interact with those sites and to imbue those com pounds with favorable drug properties, the scientists use modeling programs such as Analog and QikProp, developed by Yale University chemistry professor William L. Jorgensen and coworkers and customized
ments by research ers at sev eral J & J P R D and Janssen Pharmaceutica sites and at Tibotec, in Mechelen, Belgium, in collaboration with Arnold's group. A Phase II clini cal trial of one of these, TMC278 (rilpivirine), is currently recruiting patients, and a Phase III trial of another, TMC125 (etravirine), is starting. In 1985, Arnold also was part of a team that obtained the first structure of a vi rus that infects animals, the cold-causing Fragments R
^SH
Extender X-i S-R
4 Screen and identify ligands
Target protein
Protein-extender complex
X = leaving group R = functional groups
•i·
