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Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors. [ABSTRACT FROM AUTHOR]

Thiazole ring is an important active molecular skeleton of drugs. Thiazole in natural products and drugs are usually harmlessly eliminated. However, hepatotoxic reactions may occur due to the biological activation of thiazole to produce reactive thioamide. A typical example is hepatotoxic sudoxicam and safety meloxicam. The only structural difference between them is a methyl group on C5 position of thiazole in meloxicam. The molecular basis for the difference remains unknown and the bioactivation mechanism of the thiazole ring is still obscure. Quantum chemical calculations were performed to elucidate the activation mechanism of the thiazole ring under P450 catalysis, and the influence of the substituents on the activation pathways of thiazole ring was also studied. The calculated results show that the activation of thiazole is closely related to the substituents on the thiazole and spin state of Cpd I. The thiazole and substituted thiazole directly open the ring when catalyzed by doublet spin state Cpd I that catalyzed by the quartet spin state Cpd I can open the ring directly or indirectly, which is related to the substituents. Thiazoles modified with electron-donating substituents mainly undergo direct ring opening, while thiazoles modified with electron-withdrawing groups or weak electron-donating groups mainly undergo indirect ring-opening process accompanied by intermediate formation. The research results laid the foundation for the design of thiazole ring drugs, and also laid a theoretical foundation for the study of reducing the toxicity of thiazole ring drugs. [ABSTRACT FROM AUTHOR]

The structures and energies of neutral and charged arsenic sulfides As nS (−1,0,+1) ( n = 1–7) were systematically investigated using the G3 method. The bonding properties and the stabilities of As nS and their ions were discussed. The adiabatic electron affinities (AEAs) and adiabatic ionization potentials (AIPs) were presented. The ground-state structures of As nS can be considered as the lowest-energy structure of neutral As n+1 by replacing an As atom with a S atom, that is, “substitutional structure”, in which the feature of sulfur bonding is edge-bridging. The ground-state structures of As nS + tend to be derived from the lowest-energy structure of cation As n+ by attaching to a S atom, that is, “attaching structure”, in which the sulfur can be three-fold coordinated. There is no rule to be found for the ground-state structure of anion As nS −, in which the sulfur can be a terminal atom. There are odd-even alternations in both AEAs and AIPs as a function of size of As nS. The dissociation energies of S, S −, and/or S + from neutral As nS and their ions were calculated to examine their stabilities. [ABSTRACT FROM AUTHOR]

Lapatinib, an orally active dual tyrosine kinase inhibitor, is efficacious in combination therapy with capecitabine for advanced metastatic breast cancer. Despite its importance, it has been associated with hepatotoxicity observed in clinical trials and postmarketing surveillance. The mechanisms of hepatotoxicity at the chemical and cellular levels may link to drug metabolism. In this study, the N- and α-carbon oxidation processes of lapatinib catalyzed by CYP3A4 were explored by density functional theory method. The calculation results show that oxidation of C6 is the primary metabolic process and carboxylic acid is the main metabolic product. Both hydroxylation of C8 and subsequent formation of primary amines are feasible. However, it is not easy for the primary amines to form active metabolites nitroso, which indicates that there are other paths for the production of nitroso. Carboxylic acid is not the main metabolite of N7 oxidation because of higher hydrolysis energy barrier of intermediate nitrone. It is worthy to study subsequent N-hydroxylation and its downstream reaction, which may be the main pathway for the formation of nitroso. These results lay the foundation for drug design and optimization. [ABSTRACT FROM AUTHOR]