The accurate prediction of protein-ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen-π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.

Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPAR gamma and PPAR delta have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPAR gamma agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high- throughput screening as a moderate partial PPARd agonist; its optimization was based on the X- ray crystal structure in complex with PPAR delta. In contrast to other PPARd agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPAR gamma/delta agonists in the low nano-molar range were then identified. One of the most active members, compound 20a, displayed EC50 values of 1.6 and 336 nm for PPAR delta and gamma, respectively. The X-ray crystal structure of its complex with PPARd confirms our design hypothesis. Compound 20a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPAR gamma agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPAR gamma/delta agonists for potential treatment of metabolic syndrome.

Mehr als die Summe der Teile: Der Superadditivitätseffekt auf ΔG beim Verknüpfen von Fragmenten wurde durch das Zerlegen von zwei fXa-Inhibitoren gleicher Fragmente und verschiedener Linker quantifiziert. Das Verknüpfen zweier Fragmente mit einer einzigen Bindung lieferte einen Linkerbeitrag von −14.0 kJ mol−1, was einer um 2.5 Größenordnungen verbesserten Affinität relativ zur Summe der ΔG-Werte der Fragmente entspricht (siehe Bild). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The inside cover picture shows the PPARδ ligand binding domain (magenta: helix; yellow: β-sheet) with a partial PPARδ/γ agonist (orange) exhibiting a novel binding mode. These nuclear receptors are therapeutic targets in metabolic syndrome as they regulate metabolic pathways via contact of their DNA binding domain to DNA sequences (left: from PDB 3E00). Detailed LBD–ligand interactions (right) enabled lead optimization to give potent agonists. For more information, see the Full Paper by Stefanie Keil et al. on p. 633 ff.

Unsymmetric, N-substituted benzimidazoles and imidazopyridines can be prepared directly from 2-halonitroarenes and amides through Pd(TFA)(2)/(R)-BINAP-catalyzed cross-coupling and subsequent reductive aminocyclization. This sequence can be conducted by a one-pot procedure. The method is versatile and allows the straightforward, regioselective preparation of these important nitrogen heterocycles.

AbstractThe present new general palladium‐catalyzed procedure for the cross‐coupling of (hetero)aryl tosylates provides a facile access to various functionalized (hetero)aryl alkynes tolerating many functional groups.