The Other Press, February 19, 1987

<p>Energy profile (in kcal.mol^-1) of face-on path for Erlotinib bioactivation by the Cpd I model of CYP3A4 and 1A2 in the gas and solvent phases.</p

Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: A case of Erlotinib

<div><p>EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors.</p></div

Geometries of the transition state, intermediate and product for the rearrangement of Erlotinib-Cpd I adduct to produce epoxide, ketone and phenol.

<p>_S and _F denote the side-on and face-on poses, respectively.</p

The group spin density (ρ) and charge (Q) distributed on the Erlotinib moiety in the addition to Cpd I, where _d and _q represent the doublet and quartet state, respectively.

<p>The group spin density (ρ) and charge (Q) distributed on the Erlotinib moiety in the addition to Cpd I, where _d and _q represent the doublet and quartet state, respectively.</p

Geometries of the transition state and intermediate for the formation of Erlotinib quinone from phenol catalyzed by Cpd I model.

<p>Geometries of the transition state and intermediate for the formation of Erlotinib quinone from phenol catalyzed by Cpd I model.</p