Biomedical subjects

Richard D Cramer

Publications and source records attributed to Richard D Cramer.

4 recordsLinked to original sources

PubMed2004

"Lead hopping". Validation of topomer similarity as a superior predictor of similar biological activities.

Two extensive studies quantifying the ability of topomer shape similarity to forecast a variety of biological similarities are described. In a prospective trial of "lead hopping", using topomer similarity for virtual screening and queries from the patent literature, biological assays of 308 selected compounds (representing 0.03% of those available, per assay type) yielded 11 successful "lead hops" in the 13 assays attempted. The hit rate averaged over all assays was 39% ("activity"defined as inhibition > or =20% at 10 microM), significantly greater than an unexpectedly high negative control hit rate of 15%. The average "Tanimoto 2D fingerprint similarity" between query and "lead hop" structures (0.36) was little more than the Tanimoto similarity between random drug-like structures. Topomer shape and Tanimoto 2D fingerprint similarities were also compared retrospectively, in their tendencies to concentrate together potential and actual drugs reported to belong to the same "activity class", for twenty classes. Among the most similar 3% of structures (corresponding to "> or =0.85 Tanimoto" for these structures), an average of 62% of the topomer similar selection possessed a near neighbor belonging to the same activity class, roughly a one-third superiority over the "Tanimoto > or = 0.85" selection containing 48% actives in avoiding false positives. Conversely, the least similar 75% of structures contained 0.3% actives for topomer similarity vs 1.0% actives for Tanimoto 2D fingerprint similarity, a 3-fold superiority for topomers in avoiding false negatives.

Computing Methodologies↗

PubMed2003

Topomer CoMFA: a design methodology for rapid lead optimization.

To provide an objective QSAR methodology that might accelerate lead optimization, the CoMFA and topomer technologies have been merged, with surprisingly good results. A series of input structures are each broken into two or more fragments at central acyclic single bonds, while removing any core fragment structurally common to the entire series. Standard topomer 3D models are automatically constructed for each fragment, and a set of steric and electrostatic fields ("CoMFA column") is generated for each set of topomers. Application of "topomer CoMFA" to 15 3D-QSAR analyses taken from the literature (847 structures) were all successful, with an average q(2) of 0.520 (literature average q(2) = 0.636) and an average standard deviation of true prediction (SDEP) of 0.688 (literature average SDEP = 0.553) for 133 structures. Topomer CoMFA results are particularly promising as queries into virtual libraries already composed of topomer structures, to directly seek structures having increased potency. Accordingly, in 13 of the 15 such "topomer CoMFA searches" attempted, combinations of commercially offered fragments were retrieved that were predicted to be more potent than any structure described in the original publication (average predicted potency increase = 20 x), showing in principle how optimization could occur.

Adenosine↗

PubMed2002

Dbtop: topomer similarity searching of conventional structure databases.

A new topomer-based method for 3D searching of conventional structural databases is described, according to which 3D molecular structures are compared as sets of fragments or topomers, in single rule-generated conformations oriented by superposition of their fragmentation bonds. A topomer is characterized by its CoMFA-like steric shape and now also by its pharmacophoric features, in some novel ways that are detailed and discussed. To illustrate the behavior of topomer similarity searching, a new dbtop program was used to generate a topomer distance matrix for a diverse set of 26 PDE4 inhibitors and 15 serotonin receptor modulators. With the best of three parameter settings tried, within the 210 shortest topomer distances (of 1460), 94.7% involved pairs of compounds having the same biological activity, and the nearest neighbor to every compound also shared its activity. The standard similarity metric, Tanimoto coefficients of "2D fingerprints", could achieve a similar selectivity performance only for the 108 shortest distances, and three Tanimoto nearest neighbors had a different biological activity. Topomer similarity also allowed "lead-hopping" among 22 of the 26 PDE4 inhibitors, notably between rolipram and cipamfylline, while 2D fingerprints" Tanimotos recognized similarity only within generally recognized structural classes. In 370 searches of authentic high-throughput screening (HTS) data sets, the typical topomer similarity search rate was about 200 structures per s.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Topomers: a validated protocol for their self-consistent generation.

The hypothesis underlying topomer development is that describing molecular structures consistently may be at least as productive as describing them more realistically but incompletely. A general protocol is detailed for deterministically generating self-consistent shapes of molecular fragments from their topologies. These and other extensions to the topomer methodology are validated by repetition of earlier benchmark studies.

Journal Article↗