History and Evolution of the Pharmacophore Concept in Computer-Aided Drug Design

Abstract

With computer-aided drug design established as an integral part of the lead discovery and optimization process, pharmacophores have become a focal point for conceptualizing and understanding receptor-ligand interactions. In the structure-based design process, pharmacophores can be used to align molecules based on the three-dimensional arrangement of chemical features or to develop predictive models (e.g., 3D-QSAR) that correlate with the experimental activities of a given training set. Pharmacophores can be also used as search queries for retrieving potential leads from structural databases, for designing molecules with specific desired attributes, or as fingerprints for assessing similarity and diversity of molecules. This review article presents a historical perspective on the evolution and use of the pharmacophore concept in the pharmaceutical, biotechnology, and fragrances industry with published examples of how the technology has contributed and advanced the field.

Small, Nonpeptide p75NTRLigands Induce Survival Signaling and Inhibit proNGF-Induced Death

“…In addition, Maliartchouk et al (2000a) and Zaccaro et al (2005) have developed low-molecular-weight TrkA agonists through progressive modification of small cyclic peptides emulating a ␤-turn. Virtual (also called in silico) screening of chemical libraries based on the structure of protein-protein interaction sites, ligand-receptor interaction sites, or a series of known small ligands is a potentially powerful approach for the identification of novel lead compounds (for review, see Kurogi and Guner, 2001;Mason et al, 2001;Guner, 2002;Singh et al, 2002;Guner et al, 2004). To date, in the area of modulation of protein-protein interactions, virtual screening has yielded only inhibitors, including compounds inhibiting the interactions of Bak with Bcl-2 (J. L. , Bak with Bcl-x (Enyedy et al, 2001), major histocompatibility complex class II proteins with CD4 (Li et al, 1997), and very late antigen-4 with vascular cell adhesion molecule-1 (Singh et al, 2002).…”

Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A2 receptor

“…It is tempting to speculate that the apparent low affinity of glybenclamide for platelet TPRs is due to: 1 lack of one or more of the established pharmacophores of SQ29,548 (eg, the 14-position nitrogen), which means lower Acta Pharmacologica Sinica npg number of TPR amino acid recognition/interaction sites; and/ or 2 possessing a three dimensional conformation that is somewhat different from SQ29,548; especially, since glybenclamide is a flexible compound whereas SQ29,548 has a rigid chemistry, and this would impact the manner by which it docks onto the binding pocket; and/or 3 differences in the bonding energies of the two molecules. Therefore, to guide the repurposing of drugs, one should make similar structural comparisons, especially for experimental drugs with well-defined pharmacophores [45] . Based on these considerations, we believe this may represent a general paradigm that may be extended to other targets/drugs.…”

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“…Now a days pharmacophore model (has been shown in Fig. 6) development has become an important part of drug discovery, design, optimization and development 63,64 . Through the CADD, screening of Pharmacophore is performed which contains different scaffold containing compound but contains similar 3-D functional group arrangement 65,66 .…”