The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.

It is now common practice in the pharmaceutical industry to use molecular diversity selection methods. With the advent of high throughput screening and combinatorial chemistry, compounds must be rationally selected from databases of hundreds of thousands of compounds to be tested for several biological activities. We explore the differences between diversity and representativity. Validation runs were made for different diversity selection methods (such as the MaxMin function), several representativity techniques (selection of compounds closest to centroids of clusters, Kohonen neural networks, nonlinear scaling of descriptor values), and various types of descriptors (topological and 3D fingerprints) including some validated whole-molecule numerical descriptors that were chosen for their correlation with biological activities. We find that only clustering based on fingerprints or on whole-molecule descriptors gives results consistently superior to random selection in extracting a diverse set of activities from a file with potential drug molecules. The results further indicate that clustering selection from fingerprints is biased toward small molecules, a behavior that might partly explain its success over other types of methods. Using numerical descriptors instead of fingerprints removes this bias without penalising performance too much.

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A set of 32 known thrombin inhibitors representing different chemical classes has been used to evaluate the performance of two implementations of incremental construction algorithms for flexible molecular docking: DOCK 4.0 and FlexX 1.5. Both docking tools are able to dock 10-35% of our test set within 2 A of their known, bound conformations using default sampling and scoring parameters. Although flexible docking with DOCK or FlexX is not able to reconstruct all native complexes, it does offer a significant improvement over rigid body docking of single, rule-based conformations, which is still often used for docking of large databases. Docking of sets of multiple conformers of each inhibitor, obtained with a novel protocol for diverse conformer generation and selection, yielded results comparable to those obtained by flexible docking. Chemical scoring, which is an empirically modified force field scoring method implemented in DOCK 4.0, outperforms both interaction energy scoring by DOCK and the Böhm scoring function used by FlexX in rigid and flexible docking of thrombin inhibitors. Our results indicate that for reliable docking of flexible ligands the selection of anchor fragments, conformational sampling and currently available scoring methods still require improvement.

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