The pharmacophore model contains multiple functions of a specific 3D model. Each feature is usually represented as a sphere (despite changes), and the radius determines the deviation tolerance from the precise position. These functions can be marked as a single function or any logical combination of "AND," "OR," and "NOT." If a molecule can be placed in a sphere that represents the query feature, the molecule is considered a hit molecule. In general, pharmacodynamic group queries may be too complicated to find hit molecules from a given library. In this case, only certain functions that are considered essential to the activity can be matched. Adjusting molecules or facilitating molecular docking simulations are other uses of the model. Depending on the situation and the type of experiment, a variety of strategies can be used to manually build a pharmacophore model, or an automatic algorithm can be used.
Figure 1. Pharmacophore model.
|Project Name||Pharmacophore Model Construction Service|
|Samples requirement||Our pharmacophore model construction service requires you to provide specific drug construction requirements.|
|Timeline||Decide according to your needs.|
|Deliverables||We provide you with raw data and calculation result analysis service.|
||If the target structure and all its ligands are unknown, pharmacophore modeling is very difficult. Considering the large number of available protein structures and potential compound formulas is to better model pharmacophores in order to effectively cover the chemical space in any search process.|
||If only a single active molecule is known, the only option may be to use similarity queries (for example, using pharmacophore fingerprints) to retrieve similar molecules.|
||Such structure-based pharmacophore queries have multiple applications: they can be used for virtual screening, ligand binding posture prediction, and comparison of binding sites.|
||The structural information of protein receptors is known, but there is no active ligand. In this case, a putative pharmacophore model can be constructed by analyzing the chemical properties of the binding site of interest.|
The pharmacophore model is mainly used in three areas:
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A: The pharmacophore model utilizes not only the molecular topological similarity but also the functional similarity of the moieties, thus using the concept of bioisosterism (bioelectronic isomerism) to make the model more reliable. The conformation based on the pharmacophore is closer to the experimental results. Considering only the similarity of shapes between compounds would lead to incorrect prediction of binding patterns. This error is corrected if the pharmacophore characteristics of the molecule (hydrogen bond acceptor, hydrogen bond donor) are taken into account.
A: In computer-aided drug design, pharmacophore models are used in three main areas:
1. Discovery of key pharmacodynamic features of drug molecules so as to establish a clear structure activity relationship (STRUCTURE RELATIONSHIP).
2. Scaffoldhopping, a virtual screening of compound libraries by pharmacophore methods to discover new skeletal compounds with activity at the target.
3. Targetfishing by pharmacophore to predict the pharmacological spectrum of compounds, and by using pharmacophore modeling, it is possible to predict the precursor adverse effects at the early stage of drug development, thus reducing the probability of drug development failure.
A: Pharmacophore model construction include the following process:
1. Select a group of ligands that are active at the same binding site in a specific target.
2. Conformational analysis of all ligands.
3. Specify the pharmacophore characteristics.
4. Superimpose the ligand conformations to obtain a pharmacophore model.
A: Virtual receptor models are used to analyze key ligand-protein interaction sites and are used to construct 3D-QSAR models to predict the biological activity of ligands. Numerous applied studies have pointed out that virtual receptor-based 3D-QSAR models have higher accuracy in predicting the biological activity of compounds compared to classical 3D-QSAR methods (CoMFA).
A: Several molecular superposition techniques are available, such as methods based on force field properties as well as shape properties by comparing the structures of compounds (DISCO, Catalyst, LigandScout). Another conformational superposition method is the FlexS algorithm. When the FlexS algorithm is applied, the flexible compound is first split into fragments, then the anchored fragments are superimposed in a manner similar to the reference molecular interactions, and then the remaining fragments of the flexible molecule are gradually added. The flexibility of the molecule is taken into account to ensure that the stacked conformation is a lower energy conformation.