SubstituteR

The SubstituteR app is a method for the enumeration of a molecule library based on a set of inbuilt R-groups (Takeuchi et al., 2021) and externally provided control ligands.

A drug discovery program's lead optimization stage generally involves designing, synthesizing, and assaying hundreds to thousands of compounds via traditional medicinal chemistry approaches. The major limitations of this approach are (a) the difficulty in rapidly designing potent molecules that adhere to the multi-parameter optimisation (MPO) problem and (b) the relatively small number of molecules explored compared to the vast size of chemical space. To address these limitations, we have developed the R-group Enumeration Chemlet, a de novo method for the R-group-based enumeration of molecules.

Steps for SubstituteR:

1. SMILES input
2. Core selection
3. Ligand filtration

📄️ SMILES Input

The user can enter or paste the SMILES string (Figure 1).

📄️ Core Selection

This step includes two sub-options for core selection: "By molecule core" and "Use Murcko Scaffold". The "Use Murcko Scaffold" option automatically detects and enters a molecular core SMARTS (Figure 2). However, under the "By molecule core" option, a new row "Enter a molecule core SMARTS for replacement" will appear (Figure 3).

📄️ Ligand Filtration

This option provides additional support to filter focused drug-like small-molecule libraries with desired properties. When a library of all ligands with potential R-group substitution is generated, a popup screen with various ligand filtration options appears instantly (Figure 4).