Discovery of Potent Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 Using a Novel Growth-Based Protocol of in Silico Screening and Optimization in CONTOUR

Abstract

With the continuous progress in ultralarge virtual libraries which are readily accessible, it is of great interest to explore this large chemical space for hit identification and lead optimization using reliable structure-based approaches. In this work, a novel growth-based screening protocol has been designed and implemented in the structure-based design platform CONTOUR. The protocol was used to screen the ZINC database in silico and optimize hits to discover 11β-HSD1 inhibitors. In contrast to molecular docking, the virtual screening process makes significant improvements in computational efficiency without losing chemical equities through partitioning 1.8 million ZINC compounds into fragments, docking fragments to form key hydrogen bonds with anchor residues, reorganizing molecules into molecular fragment trees using matched fragments and common substructures, and then regrowing molecules with the help of developed intelligent growth features inside the protein binding site to find hits. The growth-base screening approach is validated by the high hit rate. A total of 50 compounds have been selected for testing; of these, 15 hits having diverse scaffolds are found to inhibit 11β-HSD1 with IC50 values of less than 1 μM in a biochemical enzyme assay. The best hit which exhibits an enzyme IC50 of 33 nM is further developed to a novel series of bicyclic 11β-HSD1 inhibitors with the best inhibition of enzyme IC50 of 3.1 nM. The final lead candidate exhibits IC50 values of 7.2 and 21 nM in enzyme and adipocyte assays, respectively, displayed greater than 1000-fold of selectivity over 11β-HSD2 and two other related hydroxysteroid dehydrogenases, and can serve as good starting points for further optimization to develop clinical candidates.

Shape-Based Descriptors for Efficient Structure-Based Fragment Growing

“…Liu et al use a directional shape-based descriptor in their larger fragment elaboration workflow as an initial prefilter for fragment candidates. 21 A probe of polyacetylene is used to define the depth of a binding site. This probe extends up to a maximum of 10 Å in the growth direction.…”

“…An aspect that is sometimes neglected in validation is the runtime. Although some developers do report runtimes, 8,12,13,16,21 the systems themselves are often designed to be long running noninteractive systems, which is not conducive to the iterative nature of drug design projects and prone to reduce the scientist's control over the process. This work will investigate the usefulness of directional shapebased descriptors called ray volume matrices (RVMs) as a prefilter in structural fragment-growing applications.…”

“…This bond will be referred to as the exit bond. The exit bond can be chosen based on possible reaction centers, 16 using heuristics, 21 or be left up to the user's discernment. Assuming such an exit bond has been chosen, the bond's direction defines the direction of growth.…”

“…At each such distance increment, rays at regular angle intervals to each other are created in a circular fashion perpendicular to the growing direction. Analogous to the implementation by Liu et al 21 these rays are used to describe the position of atoms in the pocket.…”

“…The cylindrical nature of the descriptor has an important advantage that can be exploited during comparison. As remarked by Liu et al 21 shifting the columns of a descriptor implicitly rotates the shape the descriptor represents. If the building-block descriptor is shifted relative to the pocket descriptor, the building-block's shape is effectively rotated inside the shape of the pocket without the need for any geometrical transformation (Figure 5).…”