One Concept, Three Implementations of 3D Pharmacophore-Based Virtual Screening: Distinct Coverage of Chemical Search Space

Abstract

Feature-based pharmacophore modeling is a well-established concept to support early stage drug discovery, where large virtual databases are filtered for potential drug candidates. The concept is implemented in popular molecular modeling software, including Catalyst, Phase, and MOE. With these software tools we performed a comparative virtual screening campaign on HSP90 and FXIa, taken from the 'maximum unbiased validation' data set. Despite the straightforward concept that pharmacophores are based on, we observed an unexpectedly high degree of variation among the hit lists obtained. By harmonizing the pharmacophore feature definitions of the investigated approaches, the exclusion volume sphere settings, and the screening parameters, we have derived a rationale for the observed differences, providing insight on the strengths and weaknesses of these algorithms. Application of more than one of these software tools in parallel will result in a widened coverage of chemical space. This is not only rooted in the dissimilarity of feature definitions but also in different algorithmic search strategies.

Molecular Docking and Structure-Based Drug Design Strategies

“…Table 3 lists some chemoinformatics tools used to estimate relevant molecular properties. [134,135] Molsoft [136] MoKa [137,138] Another LBVS approach is the use of structural features collected from known ligands to generate pharmacophore models [139]. These ligand-based 3D pharmacophore models consist of a compilation of structural properties thought to be relevant for biological activity.…”

Virtual Screening Strategies in Drug Design

“…Assim, o padrão farmacofórico irá depender do grupo de moléculas selecionadas para sua derivação. 106 Para criar um modelo farmacofórico teórico, geralmente, o espaço conformacional de cada ligante é explorado e enumerado em vários confôrmeros. Uma vez gerado, cada confôrmero será tratado como um corpo rígido durante o mapeamento do farmacóforo.…”

Pharmacophore Modeling: Methods and Applications

“…Although feature definition and annotation may seem straightforward, in practice comparative studies of different pharmacophore modeling packages [24][25][26] found substantial differences in how molecules are annotated with pharmacophore features. Different software packages may identify different protonation states of a molecule, resulting in different hydrogen bond features.…”