Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery.

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Preclinical drug discovery faces challenges with high-throughput screening (HTS) yielding suboptimal results.
• A significant gap exists between identifying initial drug hits and developing preclinical candidates.
• Investigating ligand-receptor interactions is crucial for advancing drug development.

Purpose of the Study:

• To highlight the resurgence of structure-based drug design (SBDD) in modern drug discovery.
• To discuss the role of SBDD in overcoming limitations of traditional screening methods.
• To present case studies on SBDD applied to protein kinases (PK) and G-protein coupled receptors (GPCR).

Main Methods:

• Utilizing a combination of X-ray crystallography, bioinformatics, and molecular modeling.
• Generating and validating high-quality receptor homology models.
• Screening and tailoring virtual libraries based on rational design principles.

Main Results:

• SBDD, integrating various techniques, demonstrates successful conversion of hits into drug candidates.
• Advances in understanding the role of water in binding free energy calculations.
• Demonstrated utility of SBDD for targets like protein kinases and GPCRs.

Conclusions:

• Structure-based drug design (SBDD) offers a powerful, rational approach to drug discovery.
• Synergistic application of multiple techniques enhances SBDD success rates.
• SBDD provides valuable insights into current possibilities and limitations in developing new therapeutics.