Fragment-based drug discovery using a multidomain, parallel MD-MM/PBSA screening protocol.

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• N(5)-CAIR mutase (PurE) is crucial for de novo purine synthesis.
• PurE is a promising target for novel antibacterial agent development.
• Fragment-based drug discovery requires efficient screening methods.

Purpose of the Study:

• To establish a computational screening protocol for identifying fragment-like PurE inhibitors.
• To validate the computational protocol against experimental fragment screening data.

Main Methods:

• Utilized molecular docking, GPU-accelerated molecular dynamics, and MM/PBSA for binding analysis.
• Leveraged the octameric structure of PurE to enhance screening throughput.
• Screened an in-house library of 352 compounds computationally.

Main Results:

• The computational protocol successfully identified known competitive binders.
• Theoretical predictions correlated well with experimental Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) results.
• Demonstrated the protocol's efficacy in identifying PurE inhibitors.

Conclusions:

• The developed computational screening protocol is effective for identifying novel PurE inhibitors.
• This method shows potential for accelerating the discovery of antibacterial agents targeting PurE.
• Computational screening offers a valuable approach for fragment-based drug discovery.