Theoretical studies on the binding of rhenium(I) complexes to inducible nitric oxide synthase

• Imaging of NOS in vivo with 99mTc(I) probes would allow earlier diagnosis of diseases.
• Re(I) non-radioactive surrogates display different degrees of iNOS inhibition.
• A computational study combining molecular docking, MD simulations and FEP calculations was performed to establish a structure activity relationship.
• Interactions responsible for iNOS-recognizing ability of the complexes were identified.
• Electrostatic interactions between the Re(CO)3 core and R260/R382 are a key issue.

Considering our interest in the design of innovative radiometal-based complexes for in vivo imaging of nitric oxide synthase (NOS), we have recently introduced a set of M(CO)3-complexes (M = 99mTc, Re) containing a pendant Nω-NO2-l-arginine moiety, a known inhibitor of the enzyme. Enzymatic assays with purified inducible NOS have shown that the non-radioactive surrogates with 3-(Re1; Ki = 84 μM) or 6-carbon linkers (Re2; Ki = 6 μM) are stronger inhibitors than the respective metal-free conjugates L1 (Ki = 178 μM) and L2 (Ki = 36 μM), with Re2 displaying the highest inhibitory potency. Aiming to rationalize the experimental results we have performed a molecular docking study combined with molecular dynamics (MD) simulations and free energy perturbation (FEP) calculations. The higher inhibitory potency of Re2 arises from the stronger electrostatic interactions observed between the “Re(CO)3” core and the residues Arg260 and Arg382. This interaction is only possible due to the higher flexibility of its C6-carbon spacer, which links the Nω-NO2-l-arginine moiety and the “Re(CO)3” organometallic core. Furthermore, FEP calculations were carried out and the resultant relative binding energies (ΔΔGbindcalc=0.690±0.028 kcal/mol,Re1/L1 and 1.825 ± 0.318 kcal/mol, Re2/L2) are in accordance with the experimental results (ΔΔGbindexp=0.461±0.009 kcal/mol,Re1/L1 and 1.129 ± 0.210 kcal/mol, Re2/L2); there is an energetic penalty for the transformation of the Re complexes into the ligands and this penalization is higher for the pair Re2/L2.

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