FOCUS — Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists

Abstract

Communication of data and ideas within a medicinal chemistry project on a global as well as local level is a crucial aspect in the drug design cycle. Over a time frame of eight years, we built and optimized FOCUS, a platform to produce, visualize, and share information on various aspects of a drug discovery project such as cheminformatics, data analysis, structural information, and design. FOCUS is tightly integrated with internal services that involve-among others-data retrieval systems and in-silico models and provides easy access to automated modeling procedures such as pharmacophore searches, R-group analysis, and similarity searches. In addition, an interactive 3D editor was developed to assist users in the generation and docking of close analogues of a known lead. In this paper, we will specifically concentrate on issues we faced during development, deployment, and maintenance of the software and how we continually adapted the software in order to improve usability. We will provide usage examples to highlight the functionality as well as limitations of FOCUS at the various stages of the development process. We aim to make the discussion as independent of the software platform as possible, so that our experiences can be of more general value to the drug discovery community.

Understanding Flavin-Dependent Halogenase Reactivity via Substrate Activity Profiling

“…7,10,16 Sixteen substrates for which the selectivity of RebH- was established (Fig. 5) were therefore docked into a multi-conformer model of RebH to determine if computationally inexpensive methods 35,36 could improve on a purely electronic view of RebH selectivity. Docking was performed using ICM Molsoft docking 37 and ROCS pharmacophore overlay 38 .…”

Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor

“…The approximate location of the binding cavity was therefore inherited from the crystal structures of mGlu 1 and mGlu 5 . Candidate regions of the cavity were studied in terms of their pharmacophore-like binding properties [53] and a graphical representation of where ligand atom centres should be placed for optimal interactions with the receptor was built using ICM Ligand Editor [54]. Based on the alteration of PAM and NAM pK B caused by mutations at the two acidic residues, E767 ECL2 and E837 7.32 , these residues constituted a likely site for phenylalkylamine binding.…”

Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect

“…To evaluate the steric hindrance effect, molecular volume was calculated and ligands were docked into the active site of AO receptor (PDB entry 4uhx) (Coelho et al, 2015). Focus 3.83 software (Molsoft L.L.C., San Diego, CA) was used for molecular volume calculation and docking studies (Stiefl et al, 2015). Both the ligands and the receptor were optimized in Focus before docking.…”