The triple reuptake inhibitors (TRIs) class is a class of effective inhibitors of human monoamine transporters (hMATs), which includes dopamine, norepinephrine, and serotonin transporters (hDATs, hNETs, and hSERTs). Due to the high degree of structural homology of the binding sites of those transporters, it is a great challenge to design potent TRIs with fine-tuned binding profiles. The molecular determinants responsible for the binding selectivity of TRIs to hDATs, hNETs, and hSERTs remain elusive. In this study, the solved X-ray crystallographic structure of hSERT in complex with escitalopram was used as a basis for modeling nine complexes of three representative TRIs (SEP225289, NS2359, and EB1020) bound to their corresponding targets. Molecular dynamics (MD) and effective post-trajectory analysis were performed to estimate the drug binding free energies and characterize the selective profiles of each TRI to hMATs. The common binding mode of studied TRIs to hMATs was revealed by hierarchical clustering analysis of the per-residue energy. Furthermore, the combined protein-ligand interaction fingerprint and residue energy contribution analysis indicated that several conserved and nonconserved "Warm Spots" such as S149, V328, and M427 in hDAT, F317, F323, and V325 in hNET and F335, F341, and V343 in hSERT were responsible for the TRI-binding selectivity. These findings provided important information for rational design of a single drug with better polypharmacological profiles through modulating multiple targets.

Understanding the Polypharmacological Profiles of Triple Reuptake Inhibitors by Molecular Simulation.

Special Issue on Plant Bioinformatics

\n\nStudies of Positively Selected Genes (PSGs) in microorganisms and\nmammals have provided insights into the dynamics of genome evolution and the genetic basis of\ndifferences between species by using whole genome-wide scans. Systematic investigations and\ncomparisons of PSGs in plants, however, are still limited.\n\n\n\nA systematic comparison of PSGs between the genomes of two cotton species,\nGossypium arboreum (G. arboreum) and G. raimondii, will give the key answer for revealing\nmolecular evolutionary differences in plants.\n\n\n\nGenome sequences of G. arboreum and G. raimondii were compared, including Whole\nGenome Duplication (WGD) events and genomic features such as gene number, gene length,\ncodon bias index, evolutionary rate, number of expressed genes, and retention of duplicated\ncopies.\n\n\n\nUnlike the PSGs in G. raimondii, G. arboreum comprised more PSGs, smaller gene size\nand fewer expressed gene. In addition, the PSGs evolved at a higher rate of synonymous\nsubstitutions, but were subjected to lower selection pressure. The PSGs in G. arboreum were also\nretained with a lower number of duplicate gene copies than G. raimondii after a single WGD event\ninvolving Gossypium.\n\n\n\nThese data indicate that PSGs in G. arboreum and G. raimondii differ not only in\nKa/Ks, but also in their evolutionary, structural, and expression properties, indicating that\ndivergence of G. arboreum and G. raimondii was associated with differences in PSGs in terms of\nevolutionary rates, gene length, expression patterns, and WGD retention in Gossypium.\n

Systematic Comparisons of Positively Selected Genes between Gossypium arboreum and Gossypium raimondii Genomes

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Systematic Comparisons of Positively Selected Genes between Gossypium arboreum and Gossypium raimondii Genomes