ABSTRACT
Among the computational methods fostering the enticing drug discovery enterprise, those based on ligand structure alone have become very popular nowadays because they are fast and require only a limited amount of information for evaluation. The key concept underlying the majority of ligand-based protocols is the similarity principle, which basically states that similar molecules should have similar biological properties (Maggiora and Shanmugasundaram 2011, 2014). This means that at least one molecule or a group of molecules that bind with some afnity to the intended biomolecular target must be known beforehand. The major focus then lies on three related issues: (i) devise methods for molecular representation, alignment, and feature matching (Maggiora and Shanmugasundaram, 2011), (ii) measure molecular similarity fast and accurately, and (iii) explore the structure-activity relationship (SAR) space using the chemical information contained in the ligands. The ultimate aim is to facilitate the virtual screening (VS) of chemical libraries, that is, the in silico version of the high-throughput screening (HTS) campaigns that test huge amounts of existing chemicals for their ability to bind to a given target or exert a particular effect in a biochemical, biophysical, or cellular assay (Macarron et al., 2011). One obvious advantage of VS is that
CONTENTS
4.1 Introduction ..................................................................................................99 4.1.1 Ligand-Based SAR Methods ........................................................ 101 4.1.2 Pharmacophore Modeling ............................................................ 102 4.1.3 Molecular Similarity Analysis (MSA) ......................................... 104
4.1.3.1 Shape Methods ................................................................ 104 4.1.3.2 Fingerprints and Structural Keys ................................. 111 4.1.3.3 Alternative Methods ....................................................... 113
4.2 Concluding Remarks ................................................................................. 115 References ............................................................................................................. 116
the compounds need not be physically available, so that extant repositories can be expanded to include molecules that have not been synthesized yet. The downside is that the real accessibility and/or synthetic feasibility of the proposed compound(s) should be ensured in advance to avoid false expectations.
