Structure Based Design of CYP51 Inhibitors

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Structure-based drug design (SBDD) is crucial in modern drug discovery.
• Cytochrome P450 51 (CYP51) is a validated therapeutic target for antifungal agents.
• While numerous CYP51 inhibitors exist, SBDD approaches for CYP51 are relatively recent.

Purpose of the Study:

• To present structural characteristics of CYP51 and its complexes.
• To compare fungal CYP51 co-crystal structures with protozoal CYP51 enzymes.
• To inform the rational design of novel CYP51 inhibitors.

Main Methods:

• X-ray crystallography was employed to determine co-crystal structures.
• Comparative structural analysis of CYP51-ligand complexes.
• Molecular modeling and computational approaches.

Main Results:

• Detailed structural features of CYP51 in complex with lanosterol and itraconazole.
• First reported co-crystal structures of fungal CYP51 with lanosterol and itraconazole.
• Comparison with existing protozoal CYP51 structures.

Conclusions:

• Structural insights facilitate understanding of CYP51 inhibition mechanisms.
• Comparative analysis aids in addressing drug resistance and selectivity challenges.
• This work provides a foundation for developing diverse and effective CYP51 inhibitors.