Scaffold-focused virtual screening: prospective application to the discovery of TTK inhibitors.

We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of the scaffold tree, we perform both 2D and 3D similarity searches between a query scaffold and a level 1 scaffold library derived from a 2 million compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds are selected for biochemical screening. We show that this scaffold-focused virtual screen prospectively identifies eight confirmed active compounds that are structurally differentiated from the query compound. In comparison, 100 compounds were selected for biochemical screening using a virtual screen based upon whole molecule similarity resulting in 12 confirmed active compounds that are structurally similar to the query compound. We elucidated the binding mode for four of the eight confirmed scaffold hops to TTK by determining their protein-ligand crystal structures; each represents a ligand-efficient scaffold for inhibitor design.

Scaffold diversity of exemplified medicinal chemistry space.

The scaffold diversity of 7 representative commercial and proprietary compound libraries is explored for the first time using both Murcko frameworks and Scaffold Trees. We show that Level 1 of the Scaffold Tree is useful for the characterization of scaffold diversity in compound libraries and offers advantages over the use of Murcko frameworks. This analysis also demonstrates that the majority of compounds in the libraries we analyzed contain only a small number of well represented scaffolds and that a high percentage of singleton scaffolds represent the remaining compounds. We use Tree Maps to clearly visualize the scaffold space of representative compound libraries, for example, to display highly populated scaffolds and clusters of structurally similar scaffolds. This study further highlights the need for diversification of compound libraries used in hit discovery by focusing library enrichment on the synthesis of compounds with novel or underrepresented scaffolds.

Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization.

Bioisosteric replacement and scaffold hopping are twin methods used in drug design to improve the synthetic accessibility, potency and drug like properties of a compound and to move into novel chemical space. Bioisosteric replacement involves swapping functional groups of a molecule with other functional groups that have similar biological properties. Scaffold hopping is the replacement of the core framework of a molecule with another scaffold that will improve the properties of the molecule or to find similar potent compounds that exist in novel chemical space. This review outlines the key concepts, importance and challenges of both methods using examples and comparisons of techniques available for finding bioisosteric replacements and scaffold hops. There are many methods available for bioisosteric replacement and scaffold hopping, all with their own advantages and disadvantages. Drug design projects would benefit from a combination of these methods to retrieve diverse and complimentary results. Continuing progress in these fields will allow further validation of both methods as well as the accumulation of knowledge on bioisosteres and possible scaffold replacements.

Predicting cytotoxicity from heterogeneous data sources with Bayesian learning.

BACKGROUND: We collected data from over 80 different cytotoxicity assays from Pfizer in-house work as well as from public sources and investigated the feasibility of using these datasets, which come from a variety of assay formats (having for instance different measured endpoints, incubation times and cell types) to derive a general cytotoxicity model. Our main aim was to derive a computational model based on this data that can highlight potentially cytotoxic series early in the drug discovery process. RESULTS: We developed Bayesian models for each assay using Scitegic FCFP_6 fingerprints together with the default physical property descriptors. Pairs of assays that are mutually predictive were identified by calculating the ROC score of the model derived from one predicting the experimental outcome of the other, and vice versa. The prediction pairs were visualised in a network where nodes are assays and edges are drawn for ROC scores >0.60 in both directions. We observed that, if assay pairs (A, B) and (B, C) were mutually predictive, this was often not the case for the pair (A, C). The results from 48 assays connected to each other were merged in one training set of 145590 compounds and a general cytotoxicity model was derived. The model has been cross-validated as well as being validated with a set of 89 FDA approved drug compounds. CONCLUSIONS: We have generated a predictive model for general cytotoxicity which could speed up the drug discovery process in multiple ways. Firstly, this analysis has shown that the outcomes of different assay formats can be mutually predictive, thus removing the need to submit a potentially toxic compound to multiple assays. Furthermore, this analysis enables selection of (a) the easiest-to-run assay as corporate standard, or (b) the most descriptive panel of assays by including assays whose outcomes are not mutually predictive. The model is no replacement for a cytotoxicity assay but opens the opportunity to be more selective about which compounds are to be submitted to it. On a more mundane level, having data from more than 80 assays in one dataset answers, for the first time, the question - "what are the known cytotoxic compounds from the Pfizer compound collection?" Finally, having a predictive cytotoxicity model will assist the design of new compounds with a desired cytotoxicity profile, since comparison of the model output with data from an in vitro safety/toxicology assay suggests one is predictive of the other.