Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods

Area of Science:

• Computational chemistry and drug discovery
• Structure-based drug design
• Medicinal chemistry

Background:

• Computational docking is crucial for drug discovery, but early methods had limitations.
• Existing docking programs often treated proteins as rigid, limiting accuracy.
• The need for improved docking accuracy spurred the development of new computational strategies.

Purpose of the Study:

• To describe the evolution of computational docking methods over 15 years.
• To showcase the development and application of the Fitted docking program.
• To illustrate how improved docking enables rational drug design and discovery.

Main Methods:

• Development of the Fitted program, incorporating protein flexibility, displaceable water molecules, and ligand-based pharmacophores.
• Implementation of specialized features in Fitted, including drug-zinc coordination and covalent bond formation.
• Derivation of the Impacts program from Fitted for studying drug metabolism by cytochrome P450 enzymes.

Main Results:

• Demonstrated improved docking accuracy leading to the design of bioactive molecules.
• Successfully applied Fitted to discover new classes of covalent prolyl oligopeptidase (POP) inhibitors.
• Utilized the Impacts program to reveal complex drug metabolism pathways and stereocenter isomerizations.

Conclusions:

• Advancements in computational docking, particularly the Fitted program, have significantly strengthened structure-based drug design.
• These methods have led to the discovery of multiple drug candidates, including BACE-1 inhibitors and covalent POP inhibitors.
• The continuous development of docking tools provides valuable resources for the medicinal chemistry community and accelerates drug discovery.