Biomedical subjects

Andrew C Good

Publications and source records attributed to Andrew C Good.

7 recordsLinked to original sources

PubMed2003

Analysis and optimization of structure-based virtual screening protocols (1): exploration of ligand conformational sampling techniques.

Ligand conformational flexibility has long been recognized as an important issue in virtual screening (VS). To this end, a number of different methodologies have been adapted to tackle the problem. Many of said techniques were originally designed for ligand derived pharmacophore screens, but have subsequently been fashioned for application within structure-based virtual screening (SVS). A popular adaptation is the pre-calculation of diverse ligand conformations for subsequent docking in target active sites. In this paper, we study a number of the software programs currently being used in conformer generation, analyzing their ability to regenerate known ligand binding conformations. The implications of these studies are discussed, from the perspective of VS in general and SVS in particular.

Computational Biology↗

PubMed2003

Analysis and optimization of structure-based virtual screening protocols. 2. Examination of docked ligand orientation sampling methodology: mapping a pharmacophore for success.

An important element of any structure-based virtual screening (SVS) technique is the method used to orient the ligands in the target active site. This has been a somewhat overlooked issue in recent SVS validation studies, with the assumption being made that the performance of an algorithm for a given set of orientation sampling settings will be representative for the general behavior of said technique. Here, we analyze five different SVS targets using a variety of sampling paradigms within the DOCK, GOLD and PROMETHEUS programs over a data set of approximately 10,000 noise compounds, combined with data sets containing multiple active compounds. These sets have been broken down by chemotype, with chemotype hit rate used to provide a measure of enrichment with a potentially improved relevance to real world SVS experiments. The variability in enrichment results produced by different sampling paradigms is illustrated, as is the utility of using pharmacophores to constrain sampling to regions that reflect known structural biology. The difference in results when comparing chemotype with compound hit rates is also highlighted.

Binding Sites↗

PubMed2003

Analysis and optimization of structure-based virtual screening protocols. (3). New methods and old problems in scoring function design.

Scoring function research remains a primary focus of current structure-based virtual screening (SVS) technology development. Here, we present an alternative method for scoring function design that attempts to combine crystallographic structural information with data derived from directly within SVS calculations. The technique utilizes a genetic algorithm (GA) to optimize functions based on binding property data derived from multiple virtual screening calculations. These calculations are undertaken on protein data bank (PDB) complex active sites using ligands of known binding mode in conjunction with "noise" compounds. The advantages of such an approach are that the function does not rely on assay data and that it can potentially use the "noise" binding data to recognize the sub-optimal docking interactions inherent in SVS calculations. Initial efforts in technique exploration using DOCK are presented, with comparisons made to existing DOCK scoring functions. An analysis of the problems inherent to scoring function development is also made, including issues in dataset creation and limitations in descriptor utility when viewed from the perspective of docking mode resolution. The future directions such studies might take are also discussed in detail.

Algorithms↗

PubMed2002

Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents.

[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.

Cell Line↗

PubMedDate not supplied

Descriptors you can count on? Normalized and filtered pharmacophore descriptors for virtual screening.

The three-dimensional (3D) binary pharmacophore fingerprints find wide application as descriptors in applications ranging from virtual screening through library design. While the 3D content they capture is an intuitively attractive feature of such measures, maximizing their signal to noise ratio has proven to be a tricky balancing act. This issue surfaces primarily due to the potential of such fingerprints to create an explosion of pharmacophores as molecular complexity and flexibility increases. In this article, we describe a modification to the fingerprint generation process that normalizes pharmacophore occurrence frequency by the conformational ensemble size used to derive the descriptor. By including pharmacophore frequency and conformational count, the importance of a given pharmacophore is weighted by the probability of its existence within a given conformational ensemble, rather than treating each pharmacophore equally. In addition, a number of filters have been added to permit the removal of unwanted pharmacophores from the descriptor set. These filters are based on pharmacophore composition (e.g. permutations made up primarily of lipophilic and/or aromatic centers), and size (pharmacophore perimeter length relative to the largest perimeter length found in the molecule). The highly uneven nature of pharmacophore distributions across the conformational ensemble used to generate them is highlighted, as are enrichment comparisons with their binary fingerprint peers. In addition, the limitations in descriptor comparison validation are high-lighted as an illustration of the need for more extensive validation experiments.

Drug Design↗

PubMedDate not supplied

Measuring CAMD technique performance: a virtual screening case study in the design of validation experiments.

The dynamic nature and comparatively young age of computational chemistry is such that novel algorithms continue to be developed at a rapid pace. Such efforts are often wrought at the expense of extensive experimental validations of said techniques, preventing a deeper understanding of their potential utility and limitations. Here we address this issue for ligand-based virtual screening descriptors through design of validation experiments that better reflect the aims of real world application. Applying the newly defined chemotype enrichment approach, a variety of two- and three-dimensional (2D/3D) similarity descriptors have been compared extensively across data sets from four diverse target types. The inhibitors within said data sets contain molecules exhibiting a wide array of substructure functionality, size and flexibility, permitting descriptor comparison in myriad settings. Relative descriptor performance under these conditions is examined, including results obtained using more typical virtual screening validation experiments. Guidelines for optimal application of said descriptors are also discussed in the context of the results obtained, as is the potential utility of fingerprint filtering.

Computer-Aided Design↗

PubMedDate not supplied

An empirical process for the design of high-throughput screening deck filters.

A process for objective identification and filtering of undesirable compounds that contribute to high-throughput screening (HTS) deck promiscuity is described. Two methods of mapping hit promiscuity have been developed linking SMARTS-based structural queries with historical primary HTS data. The first compares an expected assay hit rate to actual hit rates. The second examines the propensity of an individual compound to hit multiple assays. Statistical evaluation of the data indicates a correlation between the resultant functional group filters and compound promiscuity. These data corroborate a number of commonly applied filters as well as producing some unexpected results. Application of these models to HTS collection triage reduced the number of in-house compounds considered for screening by 12%. The implications of these findings are further discussed in the context of the HTS screening set and combinatorial library design as well as compound acquisition.

Drug Design↗