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Chris L Waller

Publications and source records attributed to Chris L Waller.

4 recordsLinked to original sources
PubMed2004

Prediction of drug-like molecular properties: modeling cytochrome p450 interactions.

Preventing drug-drug interactions and reducing drug-related mortalities dictate cleaner and costlier medicines. The cost to bring a new drug to market has increased dramatically over the last 10 years, with post-discovery activities (preclinical and clinical) costs representing the majority of the spend. With the ever-increasing scrutiny that new drug candidates undergo in the post-discovery assessment phases, there is increasing pressure on discovery to deliver higher-quality drug candidates. Given that compound attrition in the early clinical stages can often be attributed to metabolic liabilities, it has been of great interest lately to implement predictive measures of metabolic stability/ liability in the drug design stage of discovery. The solution to this issue is wrapped in understanding the basic of the cytochrome P450 (CYP) enzymes functions and structures. Recently, experimental information on the structure of a variety of cytochrome P450 enzymes, major contributors to phase I metabolism, has become readily available. This, coupled with the availability of experimental information on substrate specificities, has lead to the development of numerous computational models (macromolecular, pharmacophore, and structure-activity) for the rationalization and prediction of CYP liabilities. A comprehensive review of these models is presented in this chapter.

Crystallography, X-Ray↗
PubMedDate not supplied

A comparative QSAR study using CoMFA, HQSAR, and FRED/SKEYS paradigms for estrogen receptor binding affinities of structurally diverse compounds.

The three-dimensional quantitative structure-activity relationship (QSAR) technique of comparative molecular field analysis (CoMFA) has demonstrated the ability to provide accurate predictions for diverse chemical compounds when trained with molecules of diverse chemical type. Although predictive, the derivation and utilization of models of this type are quite computationally and person power intensive. It is this intensity that pragmatically limits the widespread implementation of these models as predictive tools. In this study, two newer QSAR techniques were evaluated as possible alternatives to CoMFA based QSAR models for the purpose of rapidly identifying estrogen receptor ligands from diverse collections of molecules. The first of these is Hologram QSAR, or HQSAR. HQSAR utilizes Tripos molecular fingerprints as descriptors in conjunction with partial least squares (PLS) regression and cross-validation routines. The HQSAR technique demonstrated the ability to rapidly develop QSAR models independent of the intense user input (i.e. geometry optimization, conformational analysis, and molecular superposition were not required). Second, a newly developed QSAR paradigm that utilizes Molecular Design Limited (MDL) substructure keys (SKEYS) as descriptors in combination with an evolutionary algorithm, Fast Random Elimination of Descriptors (FRED), was evaluated. By utilizing the FRED/SKEYS algorithm, a simple substructure-based QSAR model was derived that was comparable in statistical robustness and predictive ability to both CoMFA and HQSAR derived models. A comparison of the utility of these three approaches as computational tools for the rapid identification of estrogen receptor ligands as potential endocrine disruptors as assessed by model predictive ability will be described.

Algorithms↗