A binding mode hypothesis for prothioconazole binding to CYP51 derived from first principles quantum chemistry.

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Understanding protein-ligand interactions is crucial for drug and agrochemical safety and efficacy.
• Prothioconazole (PTZ) is an azole-like inhibitor of sterol 14-α demethylase (CYP51), but its binding mechanism remains unclear.
• Crystallographic data for PTZ-CYP51 complex is unavailable, necessitating alternative methods to elucidate binding modes.

Purpose of the Study:

• To hypothesize the binding mode of Prothioconazole (PTZ) to CYP51.
• To compare the binding of PTZ with its triazole metabolite, DPZ, to CYP51.
• To investigate the atomistic details of PTZ and DPZ binding to CYP51 using computational methods.

Main Methods:

• Density Functional Theory (DFT) calculations to obtain electron densities.
• Quantum Theory of Atoms in Molecules (QTAIM) analysis to study binding topology.
• Coupled cluster (DLPNO-CCSD(T)) calculations to determine binding enthalpy differences.

Main Results:

• Significant differences were observed in the binding modes of PTZ and DPZ to CYP51.
• The thiozolinthione head of PTZ binds to heme differently compared to the triazole head of DPZ.
• R- and S-enantiomers of PTZ show distinct binding patterns.
• DPZ binds more strongly to CYP51 than PTZ, with a binding enthalpy difference of approximately 11 kcal/mol.

Conclusions:

• Computational analysis provides insights into the distinct binding mechanisms of PTZ and DPZ with CYP51.
• The stronger binding of DPZ suggests potential differences in efficacy and safety profiles compared to PTZ.
• These findings contribute to a deeper understanding of CYP51 inhibition by azole-like compounds.