LSA: a local-weighted structural alignment tool for pharmaceutical virtual screening

Abstract

Similar structures having similar activities is a dogma for identifying new functional molecules. However, it is not rare that a minor structural change can cause a significant activity change. Methods to measure the molecular similarity can be classified into two categories of overall three-dimensional shape based methods and local substructure based methods. The former states the relation between overall similarity and activity, and is represented by conventional similarity algorithms. The latter states the relation between local substructure and activity, and is represented by conventional substructure match algorithms. Practically, the similarity of two molecules with similar activity depends on the contributions from both overall similarity and local substructure match. We report a new tool termed as a local-weighted structural alignment (LSA) tool for pharmaceutical virtual screening, which computes the similarity of two molecular structures by considering the contributions of both overall similarity and local substructure match. LSA consists of three steps: (1) mapping a common substructure between two molecular topological structures; (2) superimposing two three-dimensional molecular structures with substructure focus; (3) computing the similarity score based on superimposing. LSA has been validated with 102 testing compound libraries from DUD-E collection with the average AUC (the area under a receiver-operating characteristic curve) value of 0.82 and an average EF^1% (the enrichment factor at top 1%) of 27.0, which had consistently better performance than conventional approaches. LSA is implemented in C++ and run on Linux and Windows systems.

Fig. 1. A core substructure of an HDAC inhibitor. The core substructure (highlighted in red circle) is for an HDAC inhibitor (CHEMBL275089). The core substructure is the chelator “warhead” binding Zn²⁺ ion in the HDAC binding site. The rest of the molecular structure is for selective molecular recognition.

Fig. 2. The specification of substructures. The core substructure is specified from a template molecule which is as the core query substructure. One (or more) alternative core query substructure(s) is specified.

Fig. 3. The ROC curves of top-12 most performance improved targeted libraries virtual screenings using LSA and WEGA. The curves in red are for LSA and the curves in black are for WEGA.

Fig. 4. The superimposed structures. The core substructures are superimposed in the magnifier. The molecule in green is CHEMBL343068 and the other molecule is CHEMBL275089 as in Fig. 1.