Structure-based three-dimensional pharmacophores as an alternative to traditional methodologies

Abstract

Journal of Receptor, Ligand and Channel Research DovepressAbstract: Structure-based pharmacophore approaches have become widely used in drug discovery and design. This can be attributed to the development of new tools and methods over the past decade. Various tools based on different premises have been developed, including active site information in traditional pharmacophores. These tools have been widely used in virtual screening, de novo design, and lead optimization and been proven to be highly successful. Studies based on simultaneous use of structure-based pharmacophores, ligand-based pharmacophores, and docking have also come into the picture recently. Here, the development of structure-based pharmacophores as an alternative to traditional drug discovery approaches is discussed, with emphasis on the advances and latest developments in tools and success stories involving their application.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[39] Descriptors based on the concept of the pharmacophore (i.e.,t he pattern of features of am olecule responsible for its biological effect [40] )a ssess molecular similarity,i nt erms of the presenceo ra bsence of pharmacophoric features, such as positive/negativec harges,H Don/HAcc, and aromatic or hydrophobic moieties. Typically,t heir topological or spatiala rrangement is also taken into account; [34,35,41,42] hence, most pharmacophore-based descriptors are hybrids. Pharmacophore fingerprints are also common (both 2D and 3D);t ypically, they focus on three-or four-point pharmacophoric feature combinations and record all patterns of these features and topological or Euclidean distances between them.…”

Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies

“…Computer-aided drug design techniques represent a very efficient approach to provide promising results in drug discovery. Structure--based pharmacophore approach has proven to be useful for supporting in silico hit discovery, hit-to-lead expansion, and lead optimization (11,12). The protein-ligand complex based approach is specialized to gain insights into ligand-protein interactions and to identify the essential pharmacophore features necessary for optimal interaction and biological activity (13).…”

Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds

“…Ligand-based pharmacophore modeling was initially designed and is often used for traditional ligand-based virtual screening; an example is the quantitative structure–activity relationship (QSAR; Pulla et al, 2016 ). The most substantial common features shared by a group of active molecules can be easily extracted by using this method to form a good pharmacophore model to guide the further optimization of active compounds (Leach et al, 2010 ; Gaurav and Gautam, 2014 ). However, this approach is seldom used in reverse pharmacophore modeling due to the arbitrariness of pharmacophore models based on a single protein-annotated ligand.…”

“…The other two main methods, the use of only receptor structures and the use of protein-ligand complex structures, are forms of structure-based pharmacophore modeling (Gaurav and Gautam, 2014 ). In receptor-based methods, the pharmacophore features are first extracted from potential binding sites detected by specific protocols, and the pharmacophore models are then derived from the clustering of interaction point information and further refined or validated by using the input of the known ligands and their available or even calculated binding data (Chen and Lai, 2006 ).…”