Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose Errors in geometry for the top-ranked pose are less than 1 A in nearly ha

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Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.

Signal transduction by receptors with tyrosine kinase activity

Mutations in codon 12, 13, or 61 of one of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. Rapid assays for the detection of these point mutations have been developed recently and used to investigate the role mutated ras genes play in the pathogenesis of human tumors. It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly. The highest incidences are found in adenocarcinomas of the pancreas (90%), the colon (50%), and the lung (30%); in thyroid tumors (50%); and in myeloid leukemia (30%). For some tumor types a relationship may exist between the presence of a ras mutation and clinical or histopathological features of the tumor. There is some evidence that environmental agents may be involved in the induction of the mutations.

https://cancerres.aacrjournals.org/content/canres/49/17/4682.full.pdf

ras Oncogenes in Human Cancer: A Review

The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.

Regulation of the mevalonate pathway.

Glide's ability to identify active compounds in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of “druglike” decoy ligands that have been selected to be representative of what we believe is likely to be found in the compound collection of a pharmaceutical or biotechnology company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that average measures for both “early” and “global” enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand−protei...

/pdf/glide-a-new-approach-for-rapid-accurate-docking-and-scoring-5ewth20tdn.pdf

Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.

The compounds disclosed are analogs of the CAAX motif of proteins that can be modified by geranylgeranylation in vivo that selectively inhibit the geranylgeranylation of several proteins. The relatively poor activity of the compounds against the farnesyl protein transferase, which modifies several proteins important in cellular replication, allows the use of the compounds of the instant invention to treat diseases which are regulated by the function of a geranylgeranylated protein, such as certain cancers and inflammatory diseases. Further contained in this invention are chemotherapeutic compositions containing these geranylgeranyl protein transferase type I inhibitors and methods for their production.

Inhibitors of geranylgeranyl-protein transferase

[38] Inhibition of Ras function in Vitro and in Vivo using inhibitors of farnesyl-protein transferase

The present invention is directed to novel .alpha.-hydroxy-phosphonate compounds which inhibit mammalian phosphoinositide-specific phospholipase-C. The compounds are potent inflammatory and analgesic agents and may be useful for the treatment of cancer.

Inhibitors of phosphoinositide-specific phospholipase c

Oncogenic forms of Ras protein have been reported to occur in a variety of human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Active forms of Ras protein which are complexed with GTP can bind to GTPase activating protein (GAP). This binding is thought to be an important step in the cell transforming activity of Ras. According to the present invention a group of peptides have been discovered which block the binding of Ras to GAP.

Jackson B. Gibbs

Papers

Inhibitors of geranylgeranyl-protein transferase

[38] Inhibition of Ras function in Vitro and in Vivo using inhibitors of farnesyl-protein transferase

Inhibitors of phosphoinositide-specific phospholipase c

Peptide inhibitors of ras-gap interaction

Diarylether inhibitors of farnesyl-protein transferase