Ligand-based pharmacophore modeling approaches are used as a key strategy to facilitate screening of compound databases when the target or receptor does not have a three-dimensional structure, but the structures of a set of potent inhibitors are available. With years of experience, we provide customized ligand-based pharmacophore modeling service to precisely meet customer requirements.

Introduction of Ligand-Based Pharmacophore Modeling

In ligand-based pharmacophore modeling, a pharmacophore model is generated using a 3D alignment of the conformers of a set of biologically active compounds. First, a conformational space for each active ligand is created based on the flexibility of the ligand, then they are aligned and important common chemical features needed to create a pharmacophore model are identified. The conformational flexibility handling and molecular localization of ligands are key techniques for ligand pharmacophore modeling. At present, various automatic pharmacophore generators have been developed, such as Phase, HypoGen, HipHop, GASP, DISCO, GALAHAD and MOE, etc. The general steps followed by most of the programmes to recognize a pharmacophore pattern from a group of molecules that interact with a common receptor and the diverse applications of the pharmacophore concept. Ligand-based pharmacophore modeling has emerged as a key computational strategy to facilitate drug discovery in the absence of macromolecular target structures.

Fig 1. Virtual screening workflow with structure and ligand-based pharmacophore models. (Choudhury C, et al., 2019)

Services

Despite tremendous progress, two key challenges remain in ligand-based pharmacophore modeling: modeling of ligand flexibility and molecular alignment. As a leading service provider of protein engineering, Creative BioMart is committed to developing a variety of freely accessible web servers to identify similarly active molecules against specific target proteins using structure-based pharmacophore approaches. Our mission is to help clients identify promising new treatment candidates faster. Our services support de novo drug design, multi-target drug design and activity analysis to advance small molecule discovery. Ligand-based virtual pharmacophore screening service process is as follows:

(1) Selecting experimentally validated active compounds.

(2) Generating 3D conformations of ligands followed by structural alignment.

(3) Identification of structural features and functional groups involved in molecular recognition.

(4) Generation and validation of pharmacophore models using compound libraries as test datasets.

(5) Screening of natural product libraries.

Approaches of Ligand-Based Pharmacophore Modeling

Ligand-based pharmacophore modeling:

• Common feature pharmacophore modeling: using common chemical features of the most active compounds,
• 3D QSAR pharmacophore modeling: based on the chemical signatures of the most active and inactive compounds and their corresponding biological activities.

Modeling of ligand flexibility:

• Pre-counting method: Multiple conformations of each molecule are pre-computed and stored in a database.
• On-fly method: Conformational analysis during pharmacophore modeling.

Molecular arrangement:

• Point-based alignment methods: in point-based algorithms, atomic pairs, fragments, or chemical feature points are usually superimposed using a least-squares fit.
• Attribute-based alignment methods: attribute-based algorithms utilize molecular field descriptors (usually represented by a set of Gaussian functions) to generate alignments.

Creative BioMart is committed to providing global customers with high-quality ligand-based pharmacophore modeling service to virtually screen compound libraries, characterize the binding of existing lead compounds, and optimize their performance. 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.

Reference

1. Choudhury, C., & Narahari Sastry, G. (2019). Pharmacophore modelling and screening: concepts, recent developments and applications in rational drug design. In Structural bioinformatics: Applications in preclinical drug discovery process (pp. 25-53). Springer, Cham.

• Structure-Based Pharmacophore Modeling