When the ligand interacts with the macromolecular target, the active conformation with geometric and energy matching with the target should be generated. The pharmacophore is regarded as the greatest common denominator of the molecular interaction characteristics shared by a group of active molecules. Each type of atom or group in the ligand that exhibits certain properties associated with molecular recognition can be mapped to pharmacophore features, such as hydrophobic regions, hydrogen bond acceptors/donors, aromatic ring systems, negatively ionizable groups, positively ionizable groups, and any possible combination.
Pharmacophore modeling is a multifunctional subfield of computer-aided drug design (CADD). With the advanced CADD platform, Creative Biostructure can offer the pharmacophore modeling solution, which has many diverse applications in drug discovery programs, for instance, change the scaffold into novel compounds with a similar target, assist in virtual screening for new inhibitors, perform compound ADME/Tox analysis, and study possible off-targets.
Figure 1. Pharmacophore modeling approaches based on the available data. (Schaller D.; et al. 2020)
Based on the information available in a project, there are two basic approaches for pharmacophore modeling:
This approach has become a crucial computational strategy to facilitate drug discovery when the macromolecular target structure is unknown. The pharmacophore model is obtained by superimposing the structures of a set of active molecules and extracting the common chemical features critical to the interaction between the ligand and the specific macromolecular target.
This approach is directly related to the 3D structure of the target or the target-ligand complex and obtains the pharmacophore model by detecting the possible interaction sites between the target and the ligand, involving the analysis of complementary chemical features and spatial relationships of the active sites, and subsequent assembly of a pharmacophore model with selected features. According to the known information of a project, we can implement this strategy based on target-ligand complexes or target macromolecules (without ligands).
Creative Biostructure's pharmacophore modeling solution has been successfully applied to virtual screening and optimization processes for targeted GPCRs. Our drug discovery experts will evaluate and design cost-effective solutions before the project starts. In addition, our CADD platform supports comprehensive drug discovery programs.