Docking and scoring--theoretically easy, practically impossible?

Area of Science:

• Computational Chemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Structure-based drug design (SBDD) is crucial in modern medicinal chemistry, accelerating drug development and leading to marketed drugs.
• Computational tools, specifically docking and scoring programs, are integral to SBDD, aiding medicinal chemists in ligand-receptor interactions.

Purpose of the Study:

• To review the current state of docking and scoring programs used in SBDD.
• To provide medicinal chemists with a guide on the reliable aspects and potential pitfalls of docking and scoring.
• To discuss the interdependence of docking and scoring processes in drug design.

Main Methods:

• The review divides the discussion into two main parts: docking and scoring.
• Docking involves receptor-ligand preparation, conformational sampling, and stereochemistry considerations.
• Scoring evaluates the generated ligand-receptor poses and their correlation with binding affinity.

Main Results:

• Key findings from evaluation studies on docking and scoring accuracy are reviewed.
• The importance of receptor and ligand preparation, including protonation, tautomerisation, and hydration, is emphasized.
• The degree of conformational sampling and its impact on prediction accuracy are discussed.

Conclusions:

• Medicinal chemists need to understand when and how to interpret docking and scoring results for reliable drug design.
• Current docking and scoring algorithms have limitations that require careful consideration.
• An outline of recent advancements in scoring functions is presented.