Compound Design by Fragment-Linking.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Fragment linking can achieve superadditive binding affinities, where the linked affinity exceeds the sum of individual affinities (linking coefficient E<1).
• However, successful fragment linking is rare, with most linking coefficients (E) being significantly greater than 1.
• Designing linkers that preserve original fragment binding poses is crucial but challenging.

Purpose of the Study:

• To improve the success rate of fragment linking in drug discovery.
• To identify optimal fragment pairing strategies for enhanced binding affinities.
• To propose computational methods for guiding fragment selection in linking strategies.

Main Methods:

• Literature review on fragment linking coefficients and success rates.
• Analysis of fragment binding modes (H-bonds, hydrophobic, van der Waals).
• Proposal of Fragment Molecular Orbital (FMO) calculations for interaction analysis.

Main Results:

• Fragment linking success is limited, with suboptimal linking coefficients being common.
• A strategy is proposed: pair fragments with distinct binding characteristics (e.g., strong H-bond binders with hydrophobic/vdW binders).
• This pairing aims to improve linker tolerance and binding pose preservation.

Conclusions:

• Selecting fragment pairs with complementary binding properties can significantly enhance the probability of successful fragment linking.
• Fragment Molecular Orbital (FMO) calculations offer a valuable tool for analyzing binding interactions and guiding fragment selection for linking.
• Optimizing fragment selection is key to overcoming challenges in linker design and synthesis for improved drug discovery outcomes.