CReM - Pharmacophore Generation

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CReM-pharm – De Novo Structure Generation Utilizing 3D Pharmacophore Models

This tool has been developed to facilitate the generation of novel molecular entities that aligned to designated 3D pharmacophore models. The generation process involves the screening of an initial fragment set, which is subsequently expanded through the CReM methodology to optimize the alignment of generated structures with the maximum number of pharmacophore features. The standalone application can be accessed at https://github.com/ci-lab-cz/crem-pharm

Users are required to upload a 3D pharmacophore model in XYZ format or insert the content of this file into the text field. The first two lines in the file may remain empty, and the subsequent lines must contain space-separated feature labels (“A” for hydrogen bond acceptor, “D” for hydrogen bond donor, “H” for hydrophobic, “a” for aromatic, “P” for positively charged center, “N” for negatively charged center, and “e” for exclusion volumes) along with their corresponding three-dimensional coordinates. Using of exclusion volumes is strongly advised to obtain more accurate conformations of the generated structures. Additionally, users must provide a set of initial pharmacophore features for the primary fragment screening. Optional physicochemical parameters may also be specified.

Limitations of the web application

As this is a demonstration version, some parameters are predetermined.

  1. radius of 1.5Å for pharmacophore features
  2. radius of 2.2Å for exclusion volumes
  3. maximum number of expansions of each structure is limited to 100
  4. number of conformers enumerated for each structure is 2
  5. The generation process is limited to a maximum duration of 5 minutes, after that the results will be presented to the user as 2D molecular structures, accompanied by additional information, and generated structures can be downloaded in 3D SDF file format.
Even in such limited settings it may find some structures mapping 5, 6 or more features. For unrestricted generation a standalone application should be used.

An example pharmacophore model of CDK2 (PDB: 2FVD) including exclusion volumes can be used for quick demonstration purposes. The model can be loaded by clicking the "Load Example" button.