A Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking (Phase), rigid receptor docking (Glide), and protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. We provide an in-depth description of our novel methodology and present results for 41 targets consisting of 415 cross-docking cases divided amongst a training and test set. For both the training and test-set, we compute binding modes with a ligand-heavy atom RMSD to within 2.5 Å or better in over 90% of cross-docking cases compared to less than 70% of cross-docking cases using our previously published induced-fit docking algorithm and less than 41% using rigid receptor docking. Applications of the predicted ligand-receptor structure in free energy perturbation calculations is demonstrated for both public data and in active drug discovery projects, both retrospectively and prospectively

Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones <i>in vitro</i>, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC₅₀ of 3 μM after 6 h

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC₅₀ of 3 μM after 6 h