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Background : Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues. Pin1 has important roles in several cellular signaling pathways, consequently impacting the development of multiple types of cancers. Methods: Based on the previously reported inhibitory activity of pentacyclic triterpenoids isolated from the gum resin of Boswellia genus against Pin1, we designed a computational experiment using molecular docking, pharmacophore filtering, and structural clustering allied to molecular dynamics (MD) simulations and binding free energy calculations to explore the inhibitory activity of new triterpenoids against Pin1 structure. Here, we report different computational evidence that triterpenoids from neem (Azadirachta indica A. Juss), such as 6-deacetylnimbinene, 6-O-acetylnimbandiol, and nimbolide, replicate the binding mode of the Pin1 substrate peptide, interacting with high affinity with the binding site and thus destabilizing the Pin1 structure. Results: Our results are supported by experimental data, and provide interesting structural insights about their molecular mechanism of action, indicating that their structural scaffolds could be used as a start point to develop new inhibitors against Pin1.

Regulation of flowering is a crucial event in the evolutionary history of angiosperms. The production of flowers is regulated through the integration of different environmental and endogenous stimuli, many of which involve the activation of different genes in a hierarchical and complex signaling network. The FLOWERING LOCUS T/TERMINAL FLOWER 1 (FT/TFL1) gene family is known to regulate important aspects of flowering in plants. To better understand the pivotal events that changed FT and TFL1 functions during the evolution of angiosperms, we reconstructed the ancestral sequences of FT/TFL1-like genes and predicted protein structures through in silico modeling to identify determinant sites that evolved in both proteins and allowed the adaptative diversification in the flowering phenology and developmental processes. In addition, we demonstrate that the occurrence of destabilizing mutations in residues located at the phosphatidylcholine binding sites of FT structure are under positive selection, and some residues of 4th exon are under negative selection, which is compensated by the occurrence of stabilizing mutations in key regions and the P-loop to maintain the overall protein stability. Our results shed light on the evolutionary history of key genes involved in the diversification of angiosperms.

Regulation of flowering is a crucial event in the evolutionary history of angiosperms. The production of flowers is regulated through the integration of different environmental and endogenous stimuli, many of which involve the activation of different genes in a hierarchical and complex signaling network. The FLOWERING LOCUS T/TERMINAL FLOWER 1 (FT/TFL1) gene family is known to regulate important aspects of flowering in plants. To better understand the pivotal events that changed FT and TFL1 functions during the evolution of angiosperms, we reconstructed the ancestral sequences of FT/TFL1-like genes and predicted protein structures to identify determinant sites that evolved in both proteins and allowed the adaptative diversification in the flowering phenology and developmental processes. Residues from the P-loop domain of the analyzed FT structures showed predominantly high destabilizing mutations which is consistent with constant selective pressure found for this region. In addition, we demonstrate that the occurrence of destabilizing mutations in residues located at the phosphatidylcholine binding sites of FT structure experience positive selection, and some residues of 4th exon are under negative selection, which is compensated by the occurrence of stabilizing mutations in key regions and the P-loop to maintain the overall protein stability. Our results shed light on the evolutionary history of key genes involved in the diversification of angiosperms.

No abstract