Object-oriented approach to drug design enabled by NMR SOLVE: first real-time structural tool for characterizing...

Area of Science:

• Drug discovery and development
• Genomics and structural biology
• Computational chemistry and cheminformatics

Background:

• Genomics efforts are rapidly increasing the number of potential protein drug targets.
• A significant gap exists between identifying protein targets and developing high-affinity inhibitors.
• Nature utilizes an object-oriented approach by reusing cofactor binding domains to create related protein families.

Purpose of the Study:

• To address the challenge of developing inhibitors for the vast number of new protein targets identified through genomics.
• To propose a systems-based drug design strategy that parallels nature's object-oriented approach to gene family design.
• To introduce Integrated Object-Oriented PharmacoEngineering (IOPE) as a novel technology for efficient inhibitor library generation.

Main Methods:

• IOPE is a three-step technology for building focused combinatorial libraries of potential enzyme inhibitors.
• Utilizes Nuclear Magnetic Resonance (NMR) data derived from representative proteins within families.
• NMR SOLVE (Structurally Oriented Library Valency Engineering) data acquisition is rapid (days) and applicable to large proteins (>170 kDa).

Main Results:

• IOPE enables the design of inhibitor libraries targeting major enzyme families and sub-families.
• The object-oriented nature of IOPE allows for retained potency when cofactor mimics are swapped.
• Facilitates a more facile transition from in vitro inhibitor potency to in vivo efficacy.

Conclusions:

• IOPE offers an efficient, object-oriented strategy for drug discovery, mirroring natural protein design.
• This approach accelerates the development of high-affinity inhibitors for numerous protein targets.
• IOPE enhances flexibility in drug design, improving the likelihood of translating in vitro results to in vivo applications.