Clonal growth characteristics and diversity patterns of different Clintonia udensis (Liliaceae) diploid and tetraploid cytotypes in the Hualongshan Mountains.

Polyploidization plays an important role in plant evolution and biodiversity. However, intraspecific polyploidy compared to interspecific polyploidy received less attention. Clintonia udensis (Liliaceae) possess diploid (2n = 2x = 14) and autotetraploid (2n = 4x = 28) cytotypes. In the Hualongshan Mountains, the autotetraploids grew on the northern slope, while the diploids grew on the southern slopes. The clonal growth characteristics and clonal architecture were measured and analyzed by field observations and morphological methods. The diversity level and differentiation patterns for two different cytotypes were investigated using SSR markers. The results showed that the clonal growth parameters, such as the bud numbers of each rhizome node and the ratio of rhizome branches in the autotetraploids were higher than those in the diploids. Both the diploids and autotetraploids appeared phalanx clonal architectures with short internodes between ramets. However, the ramets or genets of the diploids had a relatively scattered distribution, while those of the autotetraploids were relatively clumping. The diploids and autotetraploids all allocated more biomass to their vegetative growth. The diploids had a higher allocation to reproductive organs than that of autotetraploids, which indicated that the tetraploids invested more resources in clonal reproduction than diploids. The clone diversity and genetic diversity of the autotetraploids were higher than that of the diploids. Significant genetic differentiation between two different cytotypes was observed (P < 0.01). During establishment and evolution, C. udensis autotetraploids employed more clumping phalanx clonal architecture and exhibited more genetic variation than the diploids.

Optimization of virtual screening against phosphoinositide 3-kinase delta: Integration of common feature pharmacophore and multicomplex-based molecular docking.

Extensive research has accumulated which suggests that phosphatidylinositol 3-kinase delta (PI3Kδ) is closely related to the occurrence and development of various human diseases, making PI3Kδ a highly promising drug target. However, PI3Kδ exhibits high homology with other members of the PI3K family, which poses significant challenges to the development of PI3Kδ inhibitors. Therefore, in the present study, a hybrid virtual screening (VS) approach based on a ligand-based pharmacophore model and multicomplex-based molecular docking was developed to find novel PI3Kδ inhibitors. 13 crystal structures of the human PI3Kδ-inhibitor complex were collected to establish models. The inhibitors were extracted from the crystal structures to generate the common feature pharmacophore. The crystallographic protein structures were used to construct a naïve Bayesian classification model that integrates molecular docking based on multiple PI3Kδ conformations. Subsequently, three VS protocols involving sequential or parallel molecular docking and pharmacophore approaches were employed. External predictions demonstrated that the protocol combining molecular docking and pharmacophore resulted in a significant improvement in the enrichment of active PI3Kδ inhibitors. Finally, the optimal VS method was utilized for virtual screening against a large chemical database, and some potential hit compounds were identified. We hope that the developed VS strategy will provide valuable guidance for the discovery of novel PI3Kδ inhibitors.

Molecular modeling strategy for detailing the primary mechanism of action of copanlisib to PI3K: combined ligand-based and target-based approach.

Since dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is associated with the pathogenesis of cancer, inflammation, and autoimmunity, PI3K has emerged as an attractive target for drug development. Although copanlisib is the first pan-PI3K inhibitor to be approved for clinical use, the precise mechanism by which it acts on PI3K has not been fully elucidated. To reveal the binding mechanisms and structure-activity relationship between PI3K and copanlisib, a comprehensive modeling approach that combines 3D-quantitative structure-activity relationship (3D-QSAR), pharmacophore model, and molecular dynamics (MD) simulation was utilized. Initially, the structure-activity relationship of copanlisib and its derivatives were explored by constructing a 3D-QSAR. Then, the key chemical characteristics were identified by building common feature pharmacophore models. Finally, MD simulations were performed to elucidate the important interactions between copanlisib and different PI3K subtypes, and highlight the key residues for tight-binding inhibitors. The present study uncovered the principal mechanism of copanlisib's action on PI3K at the theoretical level, and these findings might provide guidance for the rational design of pan-PI3K inhibitors.Communicated by Ramaswamy H. Sarma.