The use of VRML in chemical education.

The Virtual Reality Modelling Language can be used for molecular modelling. The language provides some significant advantages in the area of chemical education; it can be used to communicate 3D concepts not normally covered by existing modelling packages, the data can be distributed to a large number of students over the web, and the viewers are free to students. The strengths and weakness of VRML in various aspects of molecular modelling are discussed.

CAAX peptidomimetic FTI-244 decreases platelet-derived growth factor receptor tyrosine phosphorylation levels and inhibits stimulation of phosphatidylinositol 3-kinase but not mitogen-activated protein kinase.

Cysteine farnesylation of the Ras carboxyl terminal tetrapeptide CAAX motif (where C = cysteine, A = leucine, isoleucine, or valine, and X = methionine or serine) is required for Ras biological activity. In this report, we describe the effects of inhibitors of farnesyltransferase (FTase), the enzyme responsible for this lipid modification, on platelet-derived growth factor (PDGF) signaling in NIH-3T3 cells. In vitro, the CAAX peptidomimetic FTI-232 exhibits potent inhibition of FTase activity (IC50 = 150 nM) and its carboxyl-methylated counterpart, FTI-244, inhibits Ras processing in vivo. Treatment of NIH-3T3 cells with FTI-244 inhibits PDGF-induced DNA synthesis but not stimulation of mitogen-activated protein kinase (MAPK). However, FTI-244 significantly reduces PDGF-induced tyrosine phosphorylation levels of PDGF receptor (PDGFR) as well as its association with, and activation of, phosphatidylinositol-3-kinase (PI-3-K), a key enzyme in PDGF-induced mitogenesis.

Design and structural requirements of potent peptidomimetic inhibitors of p21ras farnesyltransferase.

Cysteine farnesylation of the ras oncogene product, p21ras, on its carboxyl-terminal CA1A2X box (C = cysteine, A = aliphatic, and X = methionine or serine) is required for its transforming activity. p21ras farnesyltransferase (FTase), the enzyme responsible or this important posttranslational modification can be inhibited by simple CA1A2X peptides. We have synthesized a family of CA1A2X peptidomimetics where the central 2 aliphatic amino acids are replaced by a variety of spacer groups with different shapes and conformational characteristics to investigate the structural requirements of these inhibitors. The biological activities of CA1A2X peptidomimetics, where the dipeptide "A1A2" is replaced by 3- or 4-aminomethylbenzoic acid (AMBA) and 3- or 4-aminobenzoic acid (ABA), are evaluated in a p21ras FTase inhibitory assay. Peptidomimetics Cys-4-ABA-Met and Cys-3-AMBA-Met contain spacers that provide good distance correspondence of the carboxylate and ammonium separation with that of the parent KB p21ras tetrapeptide, Cys-Val-Ile-Met, and are as potent FTase inhibitors (IC50 values of 50 and 100 nM, respectively). In contrast, replacing the central dipeptide with 4-AMBA reduced FTase inhibitory activity by 17-fold whereas replacement by 3-ABA reduces inhibitory activity of the peptidomimetics by 43-fold. Cys-4-ABA-Met (IC50 = 50 nM) is 128 times more potent as a p21ras FTase inhibitor than Cys-3-ABA-Met (IC50 = 6400 nM), yet these two peptidomimetics differ only in the substitution pattern around the phenyl ring. These results coupled with computer modeling studies demonstrate that the interaction between FTase and the peptidomimetics requires precise structural and conformational characteristics; in particular, correct positioning of the Cys and Met must be respected. Furthermore, Cys-3-AMBA-Met and Cys-4-ABA-Met are true inhibitors of p21ras FTase since they are not farnesylated by this enzyme, in contrast to Cys-Val-Ile-Met, which inhibits the enzyme by acting as alternative substrate. Computer modeling studies of the potent FTase inhibitor Cys-4-ABA-Met show that a folded conformation, where the thiol and carboxylate groups are close, is not possible. Therefore a beta-turn conformation that would result in the simultaneous coordination of the Cys-thiol and Met-carboxylate to zinc ion is not important for inhibition of p21ras FTase, as previously suggested.