Best of Both Worlds: On the Complementarity of Ligand-Based and Structure-Based Virtual Screening

Virtual screening with docking is an integral component of drug design, particularly during hit finding phases. While successful prospective studies of virtual screening exist, it remains a significant challenge to identify best practices a priori due to the many factors that influence the final outcome, including targets, data sets, software, metrics, and expert knowledge of the users. This study investigates the extent to which ligand-based methods can be applied to improve structure-based methods. The use of ligand-based methods to modulate the number of hits identified using the protein–ligand complex and also the diversity of these hits from the crystallographic ligand is discussed. In this study, 40 CDK2 ligand complexes were used together with two external data sets containing both actives and inactives from GlaxoSmithKline (GSK) and actives and decoys from the Directory of Useful Decoys (DUD). Results show how ligand-based modeling can be used to select a more appropriate protein conformation for docking, as well as to assess the reliability of the docking experiment. The time gained by reducing the pool of virtual screening candidates via ligand-based similarity can be invested in more accurate docking procedures, as well as in downstream labor-intensive approaches (e.g., visual inspection) maximizing the use of the chemical and biological information available. This provides a framework for molecular modeling scientists that are involved in initiating virtual screening campaigns with practical advice to make best use of the information available to them

Applications of Systematic Molecular Scaffold Enumeration to Enrich Structure–Activity Relationship Information

Establishing structure–activity relationships (SARs) in hit identification during early stage drug discovery is important in accelerating hit confirmation and expansion. We describe the development of <i>EnCore</i>, a systematic molecular scaffold enumeration protocol using single atom mutations, to enhance the application of objective scaffold definitions and to enrich SAR information from analysis of high-throughput screening output. A list of 43 literature medicinal chemistry compound series, each containing a minimum of 100 compounds, published in the <i>Journal of Medicinal Chemistry</i> was collated to validate the protocol. Analysis using the top representative Level 1 scaffolds this list of literature compound series demonstrated that <i>EnCore</i> could mimic the scaffold exploration conducted when establishing SAR. When <i>EnCore</i> was applied to analyze an HTS library containing over 200 000 compounds, we observed that over 70% of the molecular scaffolds matched extant scaffolds within the library after enumeration. In particular, over 60% of the singleton scaffolds with only one representative compound were found to have structurally related compounds after enumeration. These results illustrate the potential of <i>EnCore</i> to enrich SAR information. A case study using literature cyclooxygenase-2 inhibitors further demonstrates the advantage of <i>EnCore</i> application in establishing SAR from structurally related scaffolds. <i>EnCore</i> complements literature enumeration methods in enabling changes to the physicochemical properties of molecular scaffolds and structural modifications to aliphatic rings and linkers. The enumerated scaffold clusters generated would constitute a comprehensive collection of scaffolds for scaffold morphing and hopping

MOESM1 of Mapping the 3D structures of small molecule binding sites

Additional file 1. A list of PDB IDs for two curated datasets utilised in this study: ATP-bound cAMP-dependent Kinase ensemble (n = 5) and the Pilot Dataset (n = 1085). Figure S1. Mean ROC curves for a series of experiments to determine the optimum site size to generate binding site patches surrounding fpocket surface atoms. Table S1. Summary of proteins from the sc-PDB (2013) that were considered in ROC retrieval studies. Table S2. Summary of the Pilot Dataset

Increasing the Coverage of Medicinal Chemistry-Relevant Space in Commercial Fragments Screening

Analyzing the chemical space coverage in commercial fragment screening collections revealed the overlap between bioactive medicinal chemistry substructures and rule-of-three compliant fragments is only ∼25%. We recommend including these fragments in fragment screening libraries to maximize confidence in discovering hit matter within known bioactive chemical space, while incorporation of nonoverlapping substructures could offer novel hits in screening libraries. Using principal component analysis, polar and three-dimensional substructures display a higher-than-average enrichment of bioactive compounds, indicating increasing representation of these substructures may be beneficial in fragment screening

Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules

We describe a computational method, plane of best fit (PBF), to quantify and characterize the 3D character of molecules. This method is rapid and amenable to analysis of large diverse data sets. We compare PBF with alternative literature methods used to assess 3D character and apply the method to diverse data sets of fragment-like, drug-like, and natural product compound libraries. We show that exemplar fragment libraries underexploit the potential of 3D character in fragment-like chemical space and that drug-like molecules in the libraries examined are predominantly 2D in character

China’s rural education in transition

Taxonomic placement of each novel genome by 16S similarity, composition (PhyloPythiaS+), and multiple marker gene similarities (Phylosift). (CSV 312 bytes

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

Supplementary materials D from Integrating regulatory surveys and citizen science to map outbreaks of forest diseases: acute oak decline in England and Wales

Testing the stocastic interpolation method using citrus dataset

survey_data_5km_1

The attached ascII format file contains locations of all detections (1) and negative locations (0) in a 5 km x 5 km grid. All cells with no data are shown with the value -999

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