UFSRAT: Ultra-fast Shape Recognition with Atom Types--the discovery of novel bioactive small molecular scaffolds for FKBP12 and 11βHSD1

Abstract

Motivation: Using molecular similarity to discover bioactive small molecules with novel chemical scaffolds can be computationally demanding. We describe Ultra-fast Shape Recognition with Atom Types (UFSRAT), an efficient algorithm that considers both the 3D distribution (shape) and electrostatics of atoms to score and retrieve molecules capable of making similar interactions to those of the supplied query.

Results: Computational optimization and pre-calculation of molecular descriptors enables a query molecule to be run against a database containing 3.8 million molecules and results returned in under 10 seconds on modest hardware. UFSRAT has been used in pipelines to identify bioactive molecules for two clinically relevant drug targets; FK506-Binding Protein 12 and 11β-hydroxysteroid dehydrogenase type 1. In the case of FK506-Binding Protein 12, UFSRAT was used as the first step in a structure-based virtual screening pipeline, yielding many actives, of which the most active shows a KD, app of 281 µM and contains a substructure present in the query compound. Success was also achieved running solely the UFSRAT technique to identify new actives for 11β-hydroxysteroid dehydrogenase type 1, for which the most active displays an IC50 of 67 nM in a cell based assay and contains a substructure radically different to the query. This demonstrates the valuable ability of the UFSRAT algorithm to perform scaffold hops.

Availability and implementation: A web-based implementation of the algorithm is freely available at http://opus.bch.ed.ac.uk/ufsrat/.

Figure 1. The four UFSRAT distributions from typed atoms.

A molecule is broken down into four distributions, consisting of all atoms, hydrophobic, hydrogen bond acceptor and hydrogen bond donor.

Figure 2. Generation of UFSRAT all atom descriptors for the P1 distribution.

The atoms in a molecule are all considered as an array of points (black open circles). P1 represents the geometric centre of the atoms (black dot). Euclidean distances are calculated to all atoms from P1 (grey lines). The 3 descriptors for the P1 distribution are the mean, variance and skew of the distance distribution.

Figure 3. The UFSRAT Scoring function.

UFSRAT descriptor values have been calculated for the molecules shown and their values input to the scoring function shown. Sqc is the similarity score between the two molecules q and c (query and candidate), M being a vector representing the 48 geometric distribution descriptors.

Figure 4. The UFSRAT workflow.

Figure 5. Carbenoxolone, 20nM inhibitor of 11β-HSD1.

Figure 6. Small molecules bound to FKBP12 in ESI-MS.

P represents FKBP12 apoprotein and P:L protein in complex with a ligand.