Optimize hit compounds within the target’s active site

SPROUT-HitOpt is suggested for those who would like to further optimize their own existing hit compounds

Key features

Specifically designed to aid in the hit optimization process of drug discovery.

Offers two ways to perform hit optimization core extension and monomer replacement.

What’s in the box?

  • Is a sophisticated tool to optimize hit compounds
  • Opens the crystal structure of target molecules in PDB format
  • Has an advanced 3D graphical visualisation tool for displaying the detected target site regions, the generated structures, the protein receptor and the boundary surface
  • Offers two modes of hit optimization:
  • Provides tools to define your core molecule by importing a structure and modifying it
  • Enables to generate your own customized monomer libraries
  • In both modes, performs a systematic and exhaustive search to produce all the solutions that satisfy the steric constraints
  • Core extension applies synthetic reactions to join monomers to the core structure
  • Provides an option to perform the core extension process remotely on a cluster by distributing the search among nodes
  • Offers tools to help you select the structures of your interest based on
    • Binding affinity scores
    • Structural complexity scores
    • Substructure search
  • Saves the results into PDB, MDL SDfile and Postscript formats
  • Supports multi-session hit optimization. This can be done by saving the results into SPROUT’s internal file format which can be reloaded at a later time in order to review your results

Hit optimization in SPROUT-HitOpt

SPROUT-HitOpt in action

HIV-1 reverse transcriptase is an enzyme utilized by the HIV virus to convert the RNA carried within the virus particle, into DNA which can be inserted into the DNA of the host cell. This is a significant target in anti-HIV therapy as blocking this conversion prevents HIV taking over white blood cells. In the example below, the 1EP4 receptor complexed with S-1153 inhibitor is used.

The first conceptual challenge is deciding on the core structure, in many cases it is acceptable to use the entire bound ligand as the core. However, for 1EP4 the ligand is already a reasonable fit for the cavity, thus extending the structure will likely introduce some steric repulsions that would be unfavourable. The core therefore should be smaller than this ligand and SPROUT-HitOpt contains tools within the ELEFANT module that allow the original ligand to be imported and edited to produce the core. It was therefore decided to remove the thioether and replace it with an alcohol that can be used to form a bi-aryl ether during core extension. This change was selected as it offers a good point of diversity because ethers are relatively easy to form and there is an abundance of available starting materials for this reaction.

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