Synergy between combinatorial chemistry and de novo design

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Traditional de novo design methods often yield ligands that are difficult to synthesize.
• Structure-based design can guide the generation of novel molecules with improved synthetic accessibility.

Purpose of the Study:

• To develop a novel structure-based de novo design strategy for combinatorial library generation.
• To ensure the designed ligands are both conformationally suitable for protein binding sites and synthetically tractable.

Main Methods:

• Integrating specific core templates into acyclic chains of variable length and bond orders.
• Exploring conformational space to link pharmacophores within protein binding sites.
• Utilizing 2D queries derived from molecular skeletons to identify compatible reagents for synthesis.

Main Results:

• A fragment connection algorithm was developed to generate "generic" 3D molecules with a central core template.
• A two-phase approach ensures compatibility of reagents with 3D conformations and binding site constraints.
• The strategy yields product molecules with desired templates and functional groups, suitable for synthesis.

Conclusions:

• The described method enhances the synthetic feasibility of de novo designed ligands.
• This approach offers a viable alternative for structure-based combinatorial library design.
• The strategy effectively balances conformational requirements with synthetic accessibility in drug discovery.