Nowadays, molecular docking technology is still the most popular structure-based drug design method, which makes full use of the protein-ligand interaction information. However, compared with molecular docking, structure-based pharmacophore methods show obvious advantages in terms of calculation cost and accuracy in virtual screening. Studies have shown that the structure-based pharmacophore model plays an essential role in the discovery of new active molecules in virtual screening. Structure-based pharmacophores are also successfully applied in molecular docking procedures to better distinguish between incorrect and correct conformations, thereby increasing the success rate of molecular docking. At Alfa Chemistry, the structure-based pharmacophore modeling generates chemical features of the active site and the sterical relationships from 3D structure of macromolecular target or macromolecule-ligand complex. It probes the possible interaction sites between the macromolecular target and the ligands.
Figure 1. Structure-based pharmacophore model generation and application. (Sanders, M.; et al. 2012)
The structure-based pharmacophore construction process includes the following steps:
Alfa Chemistry has utilized most state-of-the-art techniques and software tools for structure-based pharmacophore modeling. Depending on the situation and the type of experiment, multiple strategies are available to construct pharmacophore models. Our rapid and high-quality services are as follow:
Structure-based 3D pharmacophore identification can be performed based on two types of atomic models:
1. In the macromolecule-ligand complex, the ligand is located at the binding site of the target molecule. Ligands are either co-crystals or docked to the target binding site to obtain a complex structure with macromolecules. In addition, we can also explore new chemical spatial regions within the same binding cavity. In this case, a new 3D pharmacophore can be generated for the same active site without being affected by existing ligands.
2. Our experts can also use the atomic model to derive the 3D pharmacophore model when macromolecule-ligand complex structure is not available, or there is no known ligand for the binding site. Ab initio algorithm is applied to arrange the pharmacophore features at the binding site, and the scaffold hopping is able to be generated by the arrangement of abstract features that are not combined with any specific ligand structure.
Even though protein is the most common drug target, protein is not the only macromolecular structure analyzed in the development of 3D pharmacophores. We can generate 3D pharmacophore models based on nucleic acids. For example, a 3D pharmacophore model is generated based on the binding site of the DNA-ligand complex structure.
Feature-based methods can be used for the analysis of macromolecule-ligand complexes and empty binding sites. We use the feature-based program to analyze the target-ligand complex, and create a set of chemical and geometric rules to identify and classify the target-ligand interaction which then form the pharmacophore feature. We dock the fragments to the binding site, and select the most promising fragment docking pose to construct a 3D pharmacophore model.
At Alfa Chemistry, we use molecular interaction fields (MIF) to identify pharmacophore characteristics. In this modeling method, we place spaced grids evenly in the predefined binding cavity and place probes to sample the binding sites. These probes are selected as various molecular fragments, representing the most likely interaction between the macromolecule and the ligand functional group. Then, we calculate the energy between the probe and target structure atoms to determine the interaction site. These probes can identify sites that interact with macromolecules and produce the MIF, which describes how the interaction energy between the target and a given probe changes with the surface of the target in the form of an energy isograph. The molecular field-based program takes the point of the local minimum of MIF energy as a 'hotspot', and converts it into a pharmacophore feature according to the type of probe with the most favorable energy interaction at this point.
Our structure-based pharmacophore modeling services remarkably reduce the cost, promote further experiments, and accelerate the process of drug design for customers worldwide. Our personalized and all-around services will satisfy your innovative study demands. If you are interested in our services, please don't hesitate to contact us. We are glad to cooperate with you and witness your success!