Novel Approach for Chemotype Hopping Based on Annotated Databases of Chemically Feasible Fragments and a Prospective Case Study: New Melanin Concentrating Hormone Antagonists

Abstract

A novel strategy for chemotype hopping, based on annotated databases of chemically feasible fragments and their oriented functionalization, is presented. A three-dimensional (3D) similarity analysis of project-oriented functionalized scaffolds provides a prioritized proposal for synthesis with the most appropriate linkers and optimal regiochemistry on R-groups. This strategy maximizes the potential of proprietary and commercially available compounds. A retrospective and prospective case study, on melanin concentrating hormone (MCH) antagonists, showing the impact on the drug discovery process of this new strategy by maintaining primary activity and improving key ADME/Tox property while enhancing intellectual property (IP) position is demonstrated.

Fragment-Hopping-Based Discovery of a Novel Chemical Series of Proto-Oncogene PIM-1 Kinase Inhibitors

“…Duplicates were eliminated through the use of a customized Pipeline Pilot [30] protocol. Fragment abstraction was performed at different levels from the original compound databases by using a publically available program [28] coded in the scientific vector language (SVL) of the MOE software system [31]. Two fragmentation levels were utilized: Onion0 and Onion1.…”

“…The Onion0 fragmentation level yielded structures coming from the closest fragmentation around the central scaffold, resulting in “naked” chemotypes decorated only with their corresponding growing vectors or anchor points. Onion1 fragmentation delivered a more elaborate structure with not only the information for the atom at a distance of one atom from the central core but also the information regarding the functionality of the atom [28]. Functionalities close to the central core are sometimes a driving force in ligand-receptor interactions, together with the main chemotype.…”

“…For the Onion1 fragment DB, all anchor points were capped with methyl groups. Then, the corresponding capped Onion1 fragment DB was further utilized without additional manipulation [28].…”

“…Addressing this challenge may lead to us achieving an optimal starting point to reach our final goal: establishing PIM-1 inhibitors as therapeutic agents. To achieve this objective, the chemotype hopping strategy based on chemically feasible fragments [28], described in Figure 2, was utilized. In this case, as structural information was available, structure-based virtual screening (VS) approaches were utilized together with ligand-based three-dimensional (3D) similarity analysis to refine the prioritization process among the proposed novel scaffolds.…”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

“…Related publications and reviews appeared in 2009 on microwave-assisted of N -heterocyclic synthesis 356 and convertible isonitriles, 365 click chemistry, 358 dynamic combinatorial chemistry, 363 large scale preparation of silicon-functionalized SynPhase lanterns, 370 kinase inhibitors, 357 heat shock protein 90 inhibitors, 376 biologically active benzoannelated nitrogen heterocycles, 361 library automation and analysis, 360,368 library design, 375 NMR-ased screening, 377,378 fragement libraries and fragement hopping, 366,367,369 review of Ellman’s libraries, 374 solid-phase resin specifications, 359 microelectrode arrays for monitoring ligand-receptor binding events, 364 yactoliter-scale DNA reactor for small molecule evolution, 362 DNA encoded libraries, 379 and fluorous chemistry and separations. 380–383 …”