Pharmacophores are used as low-resolution models of off-target effects in structure-based design projects, albeit to a lesser extent. Current structure-based pharmacophore approaches replace traditional computational drug design strategies, such as ligand-based pharmacophore and docking-based approaches. With years of experience, we provide customized structure-based pharmacophore modeling service to precisely meet customer requirements.

Introduction of Structure-Based Pharmacophore Modeling

Structure-based pharmacophore modeling works directly with the three-dimensional structure of a macromolecule target or macromolecule-ligand complex. A general protocol for structure-based pharmacophore modeling involves analysis of complementary chemical features of the active site and their spatial relationships, and subsequent assembly of selected features to obtain a pharmacophore. Structure-based pharmacophore approaches use spatial information (eg, ligand pose, conformation, etc.) of the ligand complexed with the molecular target. Therefore, this method is only suitable for experimental elucidation of structures in the presence of molecular targets complexed with active ligands. Currently, structure-based pharmacophore modeling is available using various programs, including Catalyst, Ligand Scout, Pharmacophore, Pocket version 2, Snooker, etc. Recent advances in the development of structure-based pharmacophore tools have brought this approach into the spotlight for medicinal chemists, who use it extensively for de novo drug design, lead discovery, and virtual screening, providing an alternative to docking and other traditional approaches.

Fig 1. Flowchart describes the process of 3D structure-based pharmacophore model building. (Pirhadi S, et al., 2013)

Services

Despite tremendous progress, two key challenges remain in structure-based pharmacophore modeling, including consideration of receptor flexibility and selection of appropriate pharmacophore signatures from the large pool available. As a leading service provider of protein engineering, Creative BioMart develops programs to screen compounds using structure-based pharmacophore approaches. Our mission is to help clients identify promising new treatment candidates faster. The advantage of structure-based pharmacophore is that the obtained results show structural diversity and the identified lead compounds contain completely different functional groups from the original ligand of the ligand-target complex. The structure-based pharmacophore modeling service process is as follows:

(1) Preparing the protein structure.

(2) Calculating the spatially favorable positions of functional groups through hot spot analysis, and obtaining the characteristics of the pharmacophore.

Compared to docking-based screening, structure-based pharmacophore methods are much faster with similar accuracy and fewer complete failures. Therefore, structure-based pharmacophore approaches have successfully become valuable tools for lead optimization, virtual screening, scaffold hopping, and multi-target drug design.

Approaches of Ligand-Based Pharmacophore Modeling

We employ two structure-based pharmacophore modeling approaches:

• Macromolecular-ligand complex-based methods: specifically designed to detect ligand-binding sites of macromolecular targets and identify key interaction points between ligands. A limitation of this approach is that it requires the three-dimensional structure of the macromolecular ligand complex, which means that it cannot be applied to compounds without known binding sites.
• Macromolecule (ligand-free) based methods: methods to obtain pharmacophore from ligand-free proteins use only protein active site information. This approach does not encounter the challenging issues of ligand flexibility, molecular arrangement, and correct selection of training set compounds.

Creative BioMart is committed to providing global customers with high-quality structure-based pharmacophore modeling service to determine the complementary chemical characteristics of the binding site and its spatial location to screen compounds, establishing an excellent protein engineering platform for drug development. We will work with you to develop the most appropriate strategy and provide the most meaningful data for your research for accelerating the research of life sciences. If you are interested in our services, please do not hesitate to contact us for more information.

References

1. Pirhadi S, Shiri F, Ghasemi J B. (2013) Methods and applications of structure based pharmacophores in drug discovery[J]. Current topics in medicinal chemistry. 13(9): 1036-1047.
2. Gaurav A, Gautam V, Pereira S, et al.. (2014) Structure-based three-dimensional pharmacophores as an alternative to traditional methodologies[J]. Journal of Receptor Ligand and Channel Research. 7: 27-38.

• Ligand-Based Pharmacophore Modeling