Mechanistic Investigation of Lysine-Targeted Covalent Inhibition of PI3Kδ via ONIOM QM:QM Computations.

Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets, especially in oncology, and several inhibitors are currently under investigation in clinical trials for the treatment of lymphocytic leukemia, follicular lymphoma, breast, thyroid, colorectal, and lung cancer. Targeted covalent inhibitors hold significant promise for drug discovery research especially for kinases. Targeting the lysine residues attracts attention as a new strategy in designing targeted covalent inhibitors, since the lysine residue provides several advantages over the traditional cysteine residue. Recently, new highly selective covalent inhibitors of PI3Kδ with activated ester warheads, targeting the conserved Lys779 residue, were reported. Based on the observed kinetics, a covalent inhibition mechanism was proposed, but the atomistic details of the reaction are still not understood. Therefore, in the present work, we have conducted quantum chemical ONIOM M06-2X/6-31+G(d,p):PM6 calculations on the active site cluster structure of PI3Kδ to elucidate the microscopic details of the mechanism of the aminolysis reaction between Lys779 and the ester inhibitors. Our calculations clearly discriminate the noncovalent methyl ester inhibitor and the covalent inhibitors with activated phenolic esters. For the representative p-NO2, p-F, p-H, and p-OCH3 phenolic esters, the Gibbs free energy profiles of alternative mechanistic paths through either Asp782 or Asp911 demonstrate the modulatory role of active site aspartate residues. The most plausible path alters depending on the electron-withdrawing/donating nature of the p-substituted phenolate leaving group. Inhibitors with sufficiently strong electron-withdrawing group prefer direct dissociation of the leaving group from the tetrahedral zwitterion intermediate, while the ones with electron-donating group favor the formation of a neutral tetrahedral intermediate prior to the dissociation. The relative Gibbs free energy barriers of p-NO2 < p-F < p-H < p-OCH3 substituted phenyl esters display the same qualitative trend as the experimentally measured kinact/KI values. Our results provide in depth insight into the mechanism, which can pave the way for optimizing the inhibitor efficiency.

Influence of ionic liquids on the electronic environment of atomically dispersed Ir on (MgO)(100).

Recently, ionic liquids (ILs) have been used as ligands for single-site Ir(CO)2 complexes bound to metal-oxide supports because of their electron-donor/acceptor capacities. The combined effects of supports and ILs as ligands may pave the way to the tuning of the surrounding electronic properties to increase electron-donor/acceptor efficiency in metal-oxide supported Ir(CO)2 complexes. Herein, we have used Density Functional Theory to model Ir(CO)2 complexes bound to MgO supports with and without the presence of an IL to explain the role of ILs in modifying the electronic structure of the supported complex. Comparison of the ν(CO) band stretching frequencies with experimental results has led to the rationalization of the factors driving the interactions between the IL, the support, and the catalyst as well as the justification of the methodology for further studies.

Mechanistic insights into lysine-targeting covalent inhibition through a theoretical study of ester aminolysis.

Development of targeted covalent inhibitors in drug design has a broad and important interest and many efforts are currently being made in this direction. Targeted covalent inhibitors have special relevance in oncology due to the possibilities they offer to overcome the problems of acquired resistance. In recent experiments, lysine-targeting has been envisaged for the irreversible inhibition of the heterodimeric lipid kinase phosphoinositide 3-kinase delta (PI3Kδ). Activated esters have been evaluated and shown to be promising inhibitors of this enzyme, but the reaction mechanisms display specificities that are not yet fully understood. In the present work, we have carried out a theoretical study of the aminolysis reaction of model esters in aqueous solution to gain insights into the corresponding biological processes. We have found that phenolic esters bearing electron-withdrawing groups are particularly reactive. The predicted mechanism involves the formation of a tetrahedral zwitterionic intermediate, which dissociates into an alkoxide and a protonated amide, this charge separation being the driving force for the subsequent proton transfer and final product formation. Structure-reactivity relationships are reported and shown to be a useful tool for evaluating potential inhibitor candidates.

Origins of the photoinitiation capacity of aromatic thiols as photoinitiatiors: a computational study.

In this work, we report the photophysical properties of three thiol derivatives, commonly used as photoinitiators in thiol-ene free radical polymerization, the ultimate goal being to rationalize the main reason behind the photoinitiation efficiency. For this aim, time dependent density functional theory is used to simulate the absorption spectra of alkyl thiol (R-SH), thiophenol (PhSH) and p-(trifluoromethyl) thiophenol (p-CF3PhSH), describe their excited state topologies, and explore their potential energy surfaces along the S-H dissociation. Excited state calculations have shown that the S-H photolysis is achieved through the triplet excited states following intersystem crossing from the originally populated singlet manifolds. More specifically, while in aromatic thiol derivatives dissociation is mainly triplet-state mediated, the first excited singlet state and first triplet state of alkyl thiol are both dissociative and hence potentially capable of generating the photoinduced radical species. We have also justified the experimental findings concerning the photoinitiator efficiency considering both their potential energy surface topologies and the absorption intensity, in the lowest energy region.

Insight into the Thiol-yne Kinetics via a Computational Approach.

Thiol-yne reactions have drawn attention because of the click nature as well as the regular step-growth network nature of their products, despite the radical-mediated reactant. However, the factors governing the reaction pathways have not been examined using quantum chemical tools in a comprehensive manner. Thereupon, we have systematically investigated the mechanism of thiol-yne reactions, focusing on the structural influences of thiol and alkyne functionalities. The reaction kinetics, structure-reactivity relations, and E/Z diastereoselectivity of the products have been enlightened for the first cycle of the thiol-yne polymerization reaction. For this reason, a diverse set of 11 thiol-yne reactions with four thiols and eight alkynes was modeled by means of density functional theory. We performed a benchmark study and determined the M06-2X/6-31+G(d,p) level of theory as the best cost-effective methodology to model such reactions. Results reveal that spin density, the stabilities of sulfur radicals for propagation, and the stability of alkenyl intermediate radicals for the chain transfer are the determining factors of each reaction rate. Intramolecular π-π stacking interactions at transition-state structures are found to be responsible for Z diastereoselectivity.

Solvent Effects on Thiol-Ene Kinetics and Reactivity of Carbon and Sulfur Radicals.

The thiol-ene reaction is one of the fundamental reactions in biochemistry and synthetic organic chemistry. In this study, the effect of polar media on the reaction kinetics is taken into account by using the transition state theory; the reactivities of the carbon and sulfur radicals have also been rationalized by using conceptual DFT. The results have shown that the solvents have more impact on hydrogen atom transfer reactions and the chain transfer rate constant, kCT, can be increased by using nonpolar solvents, while propagation reactions are less sensitive to media. Similarly, the kP/kCT ratio can be manipulated by changing the environment in order to obtain tailor-made polymers. Regarding the DFT descriptors, the local and global electrophilicity indices are well correlated with the propagation rate constant kP, whereas the global electrophilicity index is associated with the chain transfer rate constant kCT. Overall, electrophilicity indices can be used with confidence to predict the kinetics of thiol-ene reactions.

Theoretical Investigation of the Biogenetic Pathway for Formation of Antibacterial Indole Alkaloids from Voacanga africana.

The energetic viability of the previously proposed biogenetic pathway for the formation of two unique monoterpenoid indole alkaloids, voacafricine A and B, which are present in the fruits of Voacanga africana, was investigated using density functional theory computations. The results of these calculations indicate that not only is the previously suggested pathway not energetically viable but also that an alternative biosynthetic precursor is likely.