Pharmacophore modeling is a successful yet very diverse subfield of computer-aided drug design. The concept of the pharmacophore has been widely applied to the rational design of novel drugs. In this paper, we review the computational implementation of this concept and its common usage in the drug discovery process. Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically depicting the key elements of molecular recognition. The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge. However, the pharmacophore concept is also useful for ADME-tox modeling, side effect, and off-target prediction as well as target identification. Furthermore, pharmacophores are often combined with molecular docking simulations to improve virtual screening. We conclude this review by summarizing the new areas where significant progress may be expected through the application of pharmacophore modeling; these include protein-protein interaction inhibitors and protein design. Keywords: ADME-tox, computer-aided drug design, pharmacophore fingerprint, protein design, virtual screening
What is computer-aided drug design?Drug design is an expensive and laborious process of developing new medicine. This process has its origin in herbal remedies dating back millennia.1 Only since the last century have drugs had a (semi)synthetic origin.2 The first hit compounds often lack both potency and safety, and must therefore be optimized. While historically this was a trial-and-error process, 3,4 soon rational strategies were developed to improve potency. 5,6 As with any data handling procedures, computers have become a more prominent and ubiquitous tool in drug discovery since the 1980s. The crossover between computational and pharmaceutical research is typically designated computer-aided drug design (CADD). 8,9 CADD covers a broad range of applications spanning the drug discovery pipeline, although these are highly clustered in the early phases. The main purpose of CADD is to speed up and rationalize the drug design process while reducing costs. 10 The aim of the earliest phase in drug discovery is to identify the first hit compounds, which is sometimes attempted by high-throughput screening (HTS), the testing of many thousands of compounds with a suitable activity assay. The in silico counterpart of in vitro HTS is referred to as virtual screening and aims at filtering libraries of molecules using computational methods to prioritize those most likely to be active for a given
