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Biomedical subjects

J Christopher Culberson

Publications and source records attributed to J Christopher Culberson.

7 recordsLinked to original sources
PubMed2005

Biochemical and structural characterization of a novel class of inhibitors of the type 1 insulin-like growth factor and insulin receptor kinases.

The type 1 insulin-like growth factor receptor (IGF-1R) is often overexpressed on tumor cells and is believed to play an important role in anchorage-independent proliferation. Additionally, cell culture studies have indicated that IGF-1R confers increased resistance to apoptosis caused by radiation or chemotherapeutic agents. Thus, inhibitors of the intracellular kinase domain of this receptor may have utility for the clinical treatment of cancer. As part of an effort to develop clinically useful inhibitors of IGF-1R kinase, a novel class of pyrrole-5-carboxaldehyde compounds was investigated. The compounds exhibited selectivity against the closely related insulin receptor kinase intrinsically and in cell-based assays. The inhibitors formed a reversible, covalent adduct at the kinase active site, and treatment of such adducts with sodium borohydride irreversibly inactivated the enzyme. Analysis of a tryptic digest of a covalently modified IGF-1R kinase fragment revealed that the active site Lys1003 had been reductively alkylated with the aldehyde inhibitor. Reductive alkylation of the insulin receptor kinase with one of these inhibitors led to a similarly inactivated enzyme which was examined by X-ray crystallography. The crystal structure confirmed the modification of the active site lysine side chain and revealed details of the key interactions between the inhibitor and enzyme.

Aldehydes↗
PubMed2005

Web enabling technology for the design, enumeration, optimization and tracking of compound libraries.

Motivated by the need to augment Merck's in-house small molecule collection, web-based tools for designing, enumerating, optimizing and tracking compound libraries have been developed. The path leading to the current version of this Virtual Library Tool Kit (VLTK) is discussed in context of the (then) available commercial offerings and the constraints and requirements imposed by the end users. Though the effort was initiated to simplify the tasks of designing novel, drug-like and diverse compound libraries containing between 2K-10K unique entities, it has also evolved into a powerful tool for outsourcing syntheses as well as lead identification and optimization. The web tool includes components that select reagents, analyze synthons, identify backup reagents, enumerate libraries, calculate properties, optimize libraries and finally track the synthesized compounds through biological assays. In addition to accommodating project specific designs and virtual 3D library scanning, the application includes tools for parallel synthesis, laboratory automation and compound registration.

Combinatorial Chemistry Techniques↗
PubMed2003

Molecular model of the alpha(IIb)beta(3) integrin.

A molecular model of the alpha(IIb)beta(3) integrin has been developed utilizing (i). the crystal structure of alpha(v)beta(3), (ii). homology model of the alpha(IIb) subdomain, and (iii). the docking of alpha(IIb)beta(3)/alpha(v)beta(3) dual and selective inhibitors into the putative binding sites of alpha(IIb)beta(3) and alpha(v)beta(3). Since the binding sites of these integrins are located at the interface between the two heads of the individual subunits, only the alpha(IIb)beta(3) head region is modeled. The 3D conformations of two loops in alpha(IIb), whose residues have been implicated in non-peptide ligand binding, could not be determined from homology with alpha(v) alone. Mutagenesis data and the modeling of small ligand binding contributed to the rational design of these loop conformations. The final energy minimized loop conformations exhibit permissible phi/psi angles and contribute to a binding site model of alpha(IIb)beta(3) that is consistent with both the known mutagenesis studies and in-house structure-activity relationships. The charged residues alpha(IIb):E117 and beta(3):R214 are found to dominate the ligand-protein binding interaction. The previously identified "exosite" is also identified as a hydrogen bond, hydrophobic or pi-pi interaction with Y190, similar to the recently proposed binding model of alpha(v)beta(3).

Amino Acid Sequence↗
PubMed2002

3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.

A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

Alkyl and Aryl Transferases↗
PubMedDate not supplied

Random forest: a classification and regression tool for compound classification and QSAR modeling.

A new classification and regression tool, Random Forest, is introduced and investigated for predicting a compound's quantitative or categorical biological activity based on a quantitative description of the compound's molecular structure. Random Forest is an ensemble of unpruned classification or regression trees created by using bootstrap samples of the training data and random feature selection in tree induction. Prediction is made by aggregating (majority vote or averaging) the predictions of the ensemble. We built predictive models for six cheminformatics data sets. Our analysis demonstrates that Random Forest is a powerful tool capable of delivering performance that is among the most accurate methods to date. We also present three additional features of Random Forest: built-in performance assessment, a measure of relative importance of descriptors, and a measure of compound similarity that is weighted by the relative importance of descriptors. It is the combination of relatively high prediction accuracy and its collection of desired features that makes Random Forest uniquely suited for modeling in cheminformatics.

Journal Article↗
PubMedDate not supplied

Reagent Selector: using Synthon Analysis to visualize reagent properties and assist in combinatorial library design.

Reagent Selector is an intranet-based tool that aids in the selection of reagents for use in combinatorial library construction. The user selects an appropriate reagent group as a query, for example, primary amines, and further refines it on the basis of various physicochemical properties, resulting in a list of potential reagents. The results of this selection process are, in turn, converted into synthons: the fragments or R-groups that are to be incorporated into the combinatorial library. The Synthon Analysis interface graphically depicts the chemical properties for each synthon as a function of the topological bond distance from the scaffold attachment point. Displayed in this fashion, the user is able to visualize the property space for the universe of synthons as well as that of the synthons selected. Ultimately, the reagent list that embodies the selected synthons is made available to the user for reagent procurement. Application of the approach to a sample reagent list for a G-protein coupled receptor targeted library is described.

Combinatorial Chemistry Techniques↗