Bio: Songmi Kim is an academic researcher from Gyeongsang National University. The author has contributed to research in topics: Pharmacophore & Virtual screening. The author has an hindex of 13, co-authored 33 publications receiving 425 citations. Previous affiliations of Songmi Kim include Yonsei University & Korea Institute for Advanced Study.
TL;DR: One way is described, based on a single change in a crucial protein that enabled some crucifer species to acquire improved salt tolerance, which over evolutionary time may have resulted in further changes that ultimately facilitated colonization of saline habitats.
Abstract: A crucial prerequisite for plant growth and survival is the maintenance of potassium uptake, especially when high sodium surrounds the root zone. The Arabidopsis HIGH-AFFINITY K+ TRANSPORTER1 (HKT1), and its homologs in other salt-sensitive dicots, contributes to salinity tolerance by removing Na+ from the transpiration stream. However, TsHKT1;2, one of three HKT1 copies in Thellungiella salsuginea, a halophytic Arabidopsis relative, acts as a K+ transporter in the presence of Na+ in yeast (Saccharomyces cerevisiae). Amino-acid sequence comparisons indicated differences between TsHKT1;2 and most other published HKT1 sequences with respect to an Asp residue (D207) in the second pore-loop domain. Two additional T. salsuginea and most other HKT1 sequences contain Asn (n) in this position. Wild-type TsHKT1;2 and altered AtHKT1 (AtHKT1N-D) complemented K+-uptake deficiency of yeast cells. Mutant hkt1-1 plants complemented with both AtHKT1N-D and TsHKT1;2 showed higher tolerance to salt stress than lines complemented by the wild-type AtHKT1. Electrophysiological analysis in Xenopus laevis oocytes confirmed the functional properties of these transporters and the differential selectivity for Na+ and K+ based on the n/d variance in the pore region. This change also dictated inward-rectification for Na+ transport. Thus, the introduction of Asp, replacing Asn, in HKT1-type transporters established altered cation selectivity and uptake dynamics. We describe one way, based on a single change in a crucial protein that enabled some crucifer species to acquire improved salt tolerance, which over evolutionary time may have resulted in further changes that ultimately facilitated colonization of saline habitats.
TL;DR: This study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme.
Abstract: Inhibition of chymase is likely to divulge therapeutic ways for the treatment of cardiovascular diseases, and fibrotic disorders. To find novel and potent chymase inhibitors and to provide a new idea for drug design, we used both ligand-based and structure-based methods to perform the virtual screening(VS) of commercially available databases. Different pharmacophore models generated from various crystal structures of enzyme may depict diverse inhibitor binding modes. Therefore, multiple pharmacophore-based approach is applied in this study. X-ray crystallographic data of chymase in complex with different inhibitors were used to generate four structure–based pharmacophore models. One ligand–based pharmacophore model was also developed from experimentally known inhibitors. After successful validation, all pharmacophore models were employed in database screening to retrieve hits with novel chemical scaffolds. Drug-like hit compounds were subjected to molecular docking using GOLD and AutoDock. Finally four structurally diverse compounds with high GOLD score and binding affinity for several crystal structures of chymase were selected as final hits. Identification of final hits by three different pharmacophore models necessitates the use of multiple pharmacophore-based approach in VS process. Quantum mechanical calculation is also conducted for analysis of electrostatic characteristics of compounds which illustrates their significant role in driving the inhibitor to adopt a suitable bioactive conformation oriented in the active site of enzyme. In general, this study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme. The strategy used in the current study could be appropriate to design drugs for other enzymes as well.
TL;DR: Two pharmacophore models containing six and five pharmacophoric features, respectively, are developed using the representative structures from two molecular dynamic simulations performed in Gromacs 4.0.5 package to facilitate the future discovery of HDAC8 inhibitors.
Abstract: Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design.
TL;DR: A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow water molecules in the activation of GPCRs.
Abstract: Water molecules inside a G-protein coupled receptor (GPCR) have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal water molecules in GPCR activity, we studied the A2A adenosine receptor using microsecond molecular-dynamics simulations. Our study finds that the amount of water flux across the transmembrane (TM) domain varies depending on the receptor state, and that the water molecules of the TM channel in the active state flow three times more slowly than those in the inactive state. Depending on the location in solvent-protein interface as well as the receptor state, the average residence time of water in each residue varies from ∼O(10(2)) ps to ∼O(10(2)) ns. Especially, water molecules, exhibiting ultraslow relaxation (∼O(10(2)) ns) in the active state, are found around the microswitch residues that are considered activity hotspots for GPCR function. A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow water molecules in the activation of GPCRs.
TL;DR: The results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions, which will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives.
Abstract: Stilbene urea derivatives as a novel and competitive class of non-glycosidic α-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for α-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae α-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives.
28 Jul 2005
TL;DR: This review provides a comprehensive summary of the mechanisms of salt stress responses in plants, including salt stress-triggered physiological responses, oxidative stress, salt stress sensing and signaling pathways, organellar stress, ion homeostasis, hormonal and gene expression regulation, metabolic changes, as well as salt tolerance mechanisms in halophytes.
Abstract: Soil salinity is a major environmental stress that restricts the growth and yield of crops. Understanding the physiological, metabolic, and biochemical responses of plants to salt stress and mining the salt tolerance-associated genetic resource in nature will be extremely important for us to cultivate salt-tolerant crops. In this review, we provide a comprehensive summary of the mechanisms of salt stress responses in plants, including salt stress-triggered physiological responses, oxidative stress, salt stress sensing and signaling pathways, organellar stress, ion homeostasis, hormonal and gene expression regulation, metabolic changes, as well as salt tolerance mechanisms in halophytes. Important questions regarding salt tolerance that need to be addressed in the future are discussed.
TL;DR: It was proposed that kaempferol may interact with some amino acid residues located within the active site of α-glucosidase, occupying the catalytic center of the enzyme to avoid the entrance of p-nitrophenyl-α-D- glucopyranoside and ultimately inhibiting the enzyme activity.
Abstract: α-Glucosidase is a therapeutic target for diabetes mellitus, and α-glucosidase inhibitors play a vital role in the treatments for the disease. As a kind of potentially safer α-glucosidase inhibitor, flavonoids have attached much attention currently. In this study, kaempferol was found to show a notable inhibition activity on α-glucosidase in a mixed-type manner with IC50 value of (1.16 ± 0.04) × 10(-5) mol L(-1). Analyses of fluorescence, circular dichroism and Fourier transform infrared spectra indicated that kaempferol bound to α-glucosidase with high affinity which was mainly driven by hydrogen bonds and van der Waals forces, and this binding resulted in conformational alteration of α-glucosidase. Further molecular docking study validated the experimental results. It was proposed that kaempferol may interact with some amino acid residues located within the active site of α-glucosidase, occupying the catalytic center of the enzyme to avoid the entrance of p-nitrophenyl-α-D-glucopyranoside and ultimately inhibiting the enzyme activity.
TL;DR: The molecular dissection of salinity-tolerance trait, accompanying the classical quantitative genetics, is a substantial progress in updating tools and methods for the manipulation of plant genomes.
Abstract: Salinity is a consistent factor of crop productivity loss in the world and in particular arid and semi-arid areas where the soil salinity and saline water are major problems. Plants employ various mechanisms to cope with salinity stress and activate an array of stress-responsive genes to counteract the salinity-induced osmotic and ionic stresses. Genetic improvement for salinity tolerance is challenging, and thus progress attained over the several decades has been far less than anticipated. The generation of an explosion of knowledge and technology related to genetics and genomics over the last few decades is promising in providing powerful tools for future development of salinity-tolerant cultivars. Despite a major progress in defining the underlying mechanisms of salinity tolerance, there are still major challenges to be overcome in translating and integrating the resultant information at the molecular level into plant-breeding practices. Various approaches have been suggested to improve the eff...
TL;DR: The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19, and showed how the interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding.
Abstract: Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.