cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.48364/isimip.664235.2
title: ISIMIP3a atmospheric composition input data

description: The Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) provides a framework for the collation of a consistent set of climate impact data across sectors and scales. It also provides a unique opportunity for considering interactions between climate change impacts across sectors through consistent scenarios.<br>The ISIMIP3a part of the third simulation round is dedicated to i) impact model evaluation and improvement and ii) detection and attribution of observed impacts according to the framework of IPCC AR5 Working Group II Chapter 18. To this end all simulations are driven by observed socio-economic information combined with either observed (factual) climate data or a detrended (counterfactual) version of the observed climate allowing for the generation of a “no climate change” baseline.<br>This dataset contains globally averaged marine surface annual mean CO₂ [ppm] and CH₄ [ppb] time series for driving climate impact model simulations within ISIMIP3a. On the basis of the ISIMIP3a simulation protocol experiments four time series are provided. (a) historical/obsclim (1850-2021), (b) counterclim (1901-2021), (c) spinclim (1850-2021) and transclim (1850-1900).<br>Version 1.1 of this datasets adds the files for CH₄.<br>Version 1.2 adds the values for 2020 and 2021.
description: For the historical time series CO₂ concentrations were taken from two different sources. 1850-2005 values were extracted from Meinshausen et al. (2016), see Meinshausen et al. (2011) for details, while the years 2006-2021 were filled with data from the ESRL Global Monitoring Laboratory website (Lan et al. 2023a). The counterclim time series holds the historical 1901 value of 296.13ppm for the full period whereas splinclim has the time series fixed to the 1850 concentration of 284.73ppm. The transclim series is identical to obsclim for the period 1850-1900.<br>For CH₄, the 1850-2014 values were extracted from Meinshausen et al. (2016), see Meinshausen et al. (2017) for details, while the 2015-2021 values were filled with data from the ESRL Global Monitoring Laboratory website (Lan et al. 2023b). The counterclim, spinclim and transclim series were created in the same way as for CO₂.
DOI: 10.5281/zenodo.10021808
title: Gate-controlled Near Surface Josephson Junctions
DOI: 10.5281/zenodo.10021809
title: Gate-controlled Near Surface Josephson Junctions
DOI: 10.5281/zenodo.10401032
title: Gate-controlled Near Surface Josephson Junctions
DOI: 10.5281/zenodo.10181306
title: Gamma oscillatory complexity convey behavioral information in hippocampal networks

description: Gamma Elements table generation and analysis for Douchamps et al., 2024
DOI: 10.5281/zenodo.10181305
title: Gamma oscillatory complexity convey behavioral information in hippocampal networks

description: Gamma Elements table generation and analysis for Douchamps et al., 2024
DOI: 10.6084/m9.figshare.24850008
title: Visits and removed fruits_FS_corrected.xlsx

description: Number of visits and handled fruits by frugivores in three Iberian pear, Pyrus bourgaeana, populations as revealed by camera trapping. This is a revised improved version.
DOI: 10.6084/m9.figshare.24850008.v1
title: Visits and removed fruits_FS_corrected.xlsx

description: Number of visits and handled fruits by frugivores in three Iberian pear, Pyrus bourgaeana, populations as revealed by camera trapping. This is a revised improved version.
DOI: 10.6084/m9.figshare.23742231.v1
title: Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes

description: Excel file containing all raw data, Origin Lab files for each independent panel, and raw images.Data are related to:Figure 1: Patch-clamp recordings on CTRL and DETUB cells.Figure 2: In silico prediction of TT membrane excitability.Figure 3: All-optical AP recording in TT und SS membrane sites of CTRL cardiomyocytes. Figure 4: All-optical AP recording in TT und SS membrane sites of DETUB cardiomyocytes.Figure 5: Loss of excitability of detached t-tubules.
DOI: 10.6084/m9.figshare.22193495
title: Identification of novel human nicotinamide N-methyltransferase inhibitors: a structure-based pharmacophore modeling and molecular dynamics approach

description: Human nicotinamide N-methyltransferase (hNNMT) is a cytosolic enzyme associated in the phase-II metabolism, belonging to the S-adenosyl-L-methionine (SAM)-dependent methyltransferases family. Overexpression of hNNMT was observed in diseases such as metabolic disorders and different types of cancers, which suggest NNMT as a prospective therapeutic target. In this study we propose a structure-based pharmacophore model to understand the structural features responsible for the pharmacological activity. The generated model was validated using the ROC curve (AUC), goodness of hit score (GH), specificity, sensitivity and enrichment factor (EF). The pharmacophore was employed to retrieve active molecules from the ZINC database, followed by virtual-screening and molecular docking. Six molecules with the best pharmfit score, binding energy and ADMET properties were identified in this study. A 150 ns molecular dynamics simulation was performed on the selected molecules complexed with hNNMT protein to validate the results. The molecules ZINC35464499, ZINC13311192, ZINC31159282, ZINC14650833, ZINC14819515 and ZINC00303881 were identified, which could be act as the potential hNNMT inhibitors and can also be used as direct hits for developing novel hNNMT antagonists. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22193495.v1
title: Identification of novel human nicotinamide N-methyltransferase inhibitors: a structure-based pharmacophore modeling and molecular dynamics approach

description: Human nicotinamide N-methyltransferase (hNNMT) is a cytosolic enzyme associated in the phase-II metabolism, belonging to the S-adenosyl-L-methionine (SAM)-dependent methyltransferases family. Overexpression of hNNMT was observed in diseases such as metabolic disorders and different types of cancers, which suggest NNMT as a prospective therapeutic target. In this study we propose a structure-based pharmacophore model to understand the structural features responsible for the pharmacological activity. The generated model was validated using the ROC curve (AUC), goodness of hit score (GH), specificity, sensitivity and enrichment factor (EF). The pharmacophore was employed to retrieve active molecules from the ZINC database, followed by virtual-screening and molecular docking. Six molecules with the best pharmfit score, binding energy and ADMET properties were identified in this study. A 150 ns molecular dynamics simulation was performed on the selected molecules complexed with hNNMT protein to validate the results. The molecules ZINC35464499, ZINC13311192, ZINC31159282, ZINC14650833, ZINC14819515 and ZINC00303881 were identified, which could be act as the potential hNNMT inhibitors and can also be used as direct hits for developing novel hNNMT antagonists. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22578828.v1
title: Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitors: a novel approach in small molecule discovery

description: The calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) plays a key role in regulation of intracellular calcium levels and signaling pathways. It is involved in activation of downstream signaling pathways that regulate various cellular processes. Dysregulation of CAMKK2 activity has been linked to various diseases including cancer, suggesting that CAMKK2 inhibitors might be beneficial in oncological, metabolic and inflammatory indications. The most pressing issues in small molecule discovery are synthesis feasibility, novel chemical structure and desired biological characteristics. To circumvent this constraint, we employed ‘DrugspaceX’ for rapid lead identification, followed by repositioning seven FDA-approved drugs for CAMKK2 inhibition. Further, first-level transformation (Set1 analogues) was performed in ‘DrugspaceX’, followed by virtual screening. The t-SNE visualization revealed that the transformations surrounding Rucaparib, Treprostinil and Canagliflozin are more promising for developing CAMKK2 inhibitors. Second, using the top-ranked Set1 analogues, Set2 analogues were generated, and virtual screening revealed the top-ranked five analogues. Among the top five Set2 analogues, DE273038_5 had the lowest docking score of −11.034 kcal/mol and SA score of 2.59, retaining the essential interactions with Hotspot residues LYS194 and VAL270 across 250 ns simulation period. When compared to the other four compounds, the ligand effectiveness score was 0.409, and the number of rotatable penalties was only three. Further, DE273038_5 after two rounds of transformations was discovered to be novel and had not been previously described in other databases. These data suggest that the new candidate DE273038_5 is likely to have inhibitory activity at the CAMKK2 active site, implying potential therapeutic use. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22285594
title: Waste to drugs: identification of pyrolysis by-products as antifungal agents against <i>Cryptococcus neoformans</i>

description: The fungi, <i>Cryptococcus neoformans</i> cause major infections such as cryptococcal meningitis and cryptococcosis. Therefore, we explored the use of Thioredoxin reductase (Trr1) from <i>C. neoformans</i> as a gene target for the development of novel antifungal agents. Trr1 plays an essential role in the survival in the oxidative environment of macrophages and is important for the virulence of <i>C. neoformans</i>. During the thermochemical conversion (pyrolysis) of lignocellulosic biomass (LCB), a cocktail of compounds is produced by the decomposition and degradation. In general, LCB-derived cocktail of compounds is a rich source of aromatic compounds that have been shown to be antifungal in nature. Usually, the aqueous phase produced during biomass pyrolysis is generally regarded as waste. Here, we used <i>Parthenium hysterophorus</i> biomass as the antifungal source and obtained the aqueous phase after pyrolysis. Using GC-MS analysis of the aqueous phase collected from <i>P. hysterophorus</i> biomass revealed the presence of a large number of aromatic and organic compounds. Using virtual screening, the compounds present in the aqueous phase were docked against Trr1 using GLIDE. Two promising candidates were analyzed further by performing molecular dynamics simulation using GROMACS, to establish stable interactions. We validated the computational results with clustering analysis. We report that 2,4-Di-tertbutyl phenol and 1H-Pyrazole, 4-ethyl-3,5-dimethyl have a potent antifungal property and we postulate that they could be a potent antifungal agent against Trr1 of <i>C. neoformans.</i> Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22578828
title: Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitors: a novel approach in small molecule discovery

description: The calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) plays a key role in regulation of intracellular calcium levels and signaling pathways. It is involved in activation of downstream signaling pathways that regulate various cellular processes. Dysregulation of CAMKK2 activity has been linked to various diseases including cancer, suggesting that CAMKK2 inhibitors might be beneficial in oncological, metabolic and inflammatory indications. The most pressing issues in small molecule discovery are synthesis feasibility, novel chemical structure and desired biological characteristics. To circumvent this constraint, we employed ‘DrugspaceX’ for rapid lead identification, followed by repositioning seven FDA-approved drugs for CAMKK2 inhibition. Further, first-level transformation (Set1 analogues) was performed in ‘DrugspaceX’, followed by virtual screening. The t-SNE visualization revealed that the transformations surrounding Rucaparib, Treprostinil and Canagliflozin are more promising for developing CAMKK2 inhibitors. Second, using the top-ranked Set1 analogues, Set2 analogues were generated, and virtual screening revealed the top-ranked five analogues. Among the top five Set2 analogues, DE273038_5 had the lowest docking score of −11.034 kcal/mol and SA score of 2.59, retaining the essential interactions with Hotspot residues LYS194 and VAL270 across 250 ns simulation period. When compared to the other four compounds, the ligand effectiveness score was 0.409, and the number of rotatable penalties was only three. Further, DE273038_5 after two rounds of transformations was discovered to be novel and had not been previously described in other databases. These data suggest that the new candidate DE273038_5 is likely to have inhibitory activity at the CAMKK2 active site, implying potential therapeutic use. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22285594.v1
title: Waste to drugs: identification of pyrolysis by-products as antifungal agents against <i>Cryptococcus neoformans</i>

description: The fungi, <i>Cryptococcus neoformans</i> cause major infections such as cryptococcal meningitis and cryptococcosis. Therefore, we explored the use of Thioredoxin reductase (Trr1) from <i>C. neoformans</i> as a gene target for the development of novel antifungal agents. Trr1 plays an essential role in the survival in the oxidative environment of macrophages and is important for the virulence of <i>C. neoformans</i>. During the thermochemical conversion (pyrolysis) of lignocellulosic biomass (LCB), a cocktail of compounds is produced by the decomposition and degradation. In general, LCB-derived cocktail of compounds is a rich source of aromatic compounds that have been shown to be antifungal in nature. Usually, the aqueous phase produced during biomass pyrolysis is generally regarded as waste. Here, we used <i>Parthenium hysterophorus</i> biomass as the antifungal source and obtained the aqueous phase after pyrolysis. Using GC-MS analysis of the aqueous phase collected from <i>P. hysterophorus</i> biomass revealed the presence of a large number of aromatic and organic compounds. Using virtual screening, the compounds present in the aqueous phase were docked against Trr1 using GLIDE. Two promising candidates were analyzed further by performing molecular dynamics simulation using GROMACS, to establish stable interactions. We validated the computational results with clustering analysis. We report that 2,4-Di-tertbutyl phenol and 1H-Pyrazole, 4-ethyl-3,5-dimethyl have a potent antifungal property and we postulate that they could be a potent antifungal agent against Trr1 of <i>C. neoformans.</i> Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22285503
title: Synthesis and <i>in vitro</i> anticancer activity of some 2-oxindoline derivatives as potential CDK2 inhibitors

description: Novel series of 2-oxindoline hydrazones <b>6a–h</b>, 3-hydroxy-2-oxoindolines <b>9a–d</b> and 2-oxoindolin-3-ylidenes <b>10a–d</b> were prepared and assessed for their anticancer activity towards breast cancer cell line (MCF7). Compounds <b>6c</b>, <b>6d</b>, <b>6g</b>, <b>9d</b>, <b>10a</b> and <b>10b</b> (IC<sub>50</sub> = 14.0 ± 0.7, 15.6 ± 0.7, 13.8 ± 0.7, 4.9 ± 0.2, 6.0 ± 0.3 and 10.8 ± 0.5 µM, respectively) showed the highest growth inhibition activity against MCF7 when compared to staurosporine (IC<sub>50</sub> = 14.5 ± 0.7 µM). Cell cycle analysis exposed arrest at G1 phase for compounds <b>6c</b>, <b>10</b> and <b>10b</b>, at S phase for compounds <b>6d</b> and <b>9d</b>, and at G1/S phase for compound <b>6g</b>. Apoptotic effect of compounds <b>6c</b>, <b>6d</b>, <b>6g</b>, <b>9d</b>, <b>10a</b> and <b>10b</b> was confirmed <i>via</i> their early and late apoptotic effects. A safety profile was revealed for compounds <b>6c</b>, <b>6d</b>, <b>6g</b>, <b>9d</b>, <b>10a</b> and <b>10b</b> on MCF10A treated normal cell. Also, compounds <b>6c</b> and <b>10b</b> displayed a promising CDK2 inhibition activity (IC<sub>50</sub> = 0.22 ± 0.01, 0.25 ± 0.01 µM, respectively). Also, docking study revealed comparable interactions with the native ligand (5-bromoindirubin). ADMET computational studies forecast the promising pharmacokinetic profile of the targeted compounds. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22285503.v1
title: Synthesis and <i>in vitro</i> anticancer activity of some 2-oxindoline derivatives as potential CDK2 inhibitors

description: Novel series of 2-oxindoline hydrazones <b>6a–h</b>, 3-hydroxy-2-oxoindolines <b>9a–d</b> and 2-oxoindolin-3-ylidenes <b>10a–d</b> were prepared and assessed for their anticancer activity towards breast cancer cell line (MCF7). Compounds <b>6c</b>, <b>6d</b>, <b>6g</b>, <b>9d</b>, <b>10a</b> and <b>10b</b> (IC<sub>50</sub> = 14.0 ± 0.7, 15.6 ± 0.7, 13.8 ± 0.7, 4.9 ± 0.2, 6.0 ± 0.3 and 10.8 ± 0.5 µM, respectively) showed the highest growth inhibition activity against MCF7 when compared to staurosporine (IC<sub>50</sub> = 14.5 ± 0.7 µM). Cell cycle analysis exposed arrest at G1 phase for compounds <b>6c</b>, <b>10</b> and <b>10b</b>, at S phase for compounds <b>6d</b> and <b>9d</b>, and at G1/S phase for compound <b>6g</b>. Apoptotic effect of compounds <b>6c</b>, <b>6d</b>, <b>6g</b>, <b>9d</b>, <b>10a</b> and <b>10b</b> was confirmed <i>via</i> their early and late apoptotic effects. A safety profile was revealed for compounds <b>6c</b>, <b>6d</b>, <b>6g</b>, <b>9d</b>, <b>10a</b> and <b>10b</b> on MCF10A treated normal cell. Also, compounds <b>6c</b> and <b>10b</b> displayed a promising CDK2 inhibition activity (IC<sub>50</sub> = 0.22 ± 0.01, 0.25 ± 0.01 µM, respectively). Also, docking study revealed comparable interactions with the native ligand (5-bromoindirubin). ADMET computational studies forecast the promising pharmacokinetic profile of the targeted compounds. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22290745
title: Exhaustive <i>in silico</i> design and screening of novel antipsychotic compounds with improved pharmacodynamics and blood-brain barrier permeation properties

description: Antipsychotic drugs or neuroleptics are widely used in the treatment of psychosis as a manifestation of schizophrenia and bipolar disorder. However, their effectiveness largely depends on the blood-brain barrier (BBB) permeation (pharmacokinetics) and drug-receptor pharmacodynamics. Therefore, in this study, we developed and implemented the <i>in silico</i> pipeline to design novel compounds (n = 260) as leads using the standard drug scaffolds with improved PK/PD properties from the standard scaffolds. As a result, the best candidates (n = 3) were evaluated in molecular docking to interact with serotonin and dopamine receptors. Finally, haloperidol (HAL) derivative (1‐(4‐fluorophenyl)‐4‐(4‐hydroxy‐4‐{4‐[(2‐phenyl‐1,3‐thiazol‐4‐yl)methyl]phenyl}piperidin‐1‐yl)butan‐1‐one) was identified as a “magic shotgun” lead compound with better affinity to the 5-HT<sub>2A</sub>, 5-HT<sub>1D</sub>, D<sub>2</sub>, D<sub>3</sub>, and 5-HT<sub>1B</sub> receptors than the control molecule. Additionally, this hit substance was predicted to possess similar BBB permeation properties and much lower toxicological profiles in comparison to HAL. Overall, the proposed rational drug design platform for novel antipsychotic drugs based on the BBB permeation and receptor binding might be an invaluable asset for a medicinal chemist or translational pharmacologist. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22290745.v1
title: Exhaustive <i>in silico</i> design and screening of novel antipsychotic compounds with improved pharmacodynamics and blood-brain barrier permeation properties

description: Antipsychotic drugs or neuroleptics are widely used in the treatment of psychosis as a manifestation of schizophrenia and bipolar disorder. However, their effectiveness largely depends on the blood-brain barrier (BBB) permeation (pharmacokinetics) and drug-receptor pharmacodynamics. Therefore, in this study, we developed and implemented the <i>in silico</i> pipeline to design novel compounds (n = 260) as leads using the standard drug scaffolds with improved PK/PD properties from the standard scaffolds. As a result, the best candidates (n = 3) were evaluated in molecular docking to interact with serotonin and dopamine receptors. Finally, haloperidol (HAL) derivative (1‐(4‐fluorophenyl)‐4‐(4‐hydroxy‐4‐{4‐[(2‐phenyl‐1,3‐thiazol‐4‐yl)methyl]phenyl}piperidin‐1‐yl)butan‐1‐one) was identified as a “magic shotgun” lead compound with better affinity to the 5-HT<sub>2A</sub>, 5-HT<sub>1D</sub>, D<sub>2</sub>, D<sub>3</sub>, and 5-HT<sub>1B</sub> receptors than the control molecule. Additionally, this hit substance was predicted to possess similar BBB permeation properties and much lower toxicological profiles in comparison to HAL. Overall, the proposed rational drug design platform for novel antipsychotic drugs based on the BBB permeation and receptor binding might be an invaluable asset for a medicinal chemist or translational pharmacologist. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22285506
title: Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain

description: The germline mutations in the C-terminus of CRAF kinase, particularly L603, and S612T/L613V, are associated with congenital heart disorders, for example, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The experimental data suggest that genetic alternation at position 603 impairs, while those at positions 612/613 enhance the CRAF kinase activity. However, the underlying mechanistic details by which these mutations increase or decrease kinase activity remain elusive. Therefore, we applied molecular dynamic simulation to investigate the impacts of these point mutations on the conformation of the CRAF kinase domain. The results revealed that the substitution of Leucine 603 for proline transits the kinase domain to a state that exhibits the molecular hallmarks of an inactive kinase, for example, a closed activation loop, ‘αC-helix out’ conformation and a distorted regulatory hydrophobic spine. However, two HCM-associated variants (S612T and L613V) show features of an active conformation, such as an open activation loop conformation, ‘αC-helix in’, the assembly of the hydrophobic spine, and more surface-exposed catalytic residues of phosphoryl transfer reaction. Overall, our study provides a mechanistic basis for the contradictory effects of the CRAF variants associated with HCM and DCM. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.22285506.v1
title: Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain

description: The germline mutations in the C-terminus of CRAF kinase, particularly L603, and S612T/L613V, are associated with congenital heart disorders, for example, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The experimental data suggest that genetic alternation at position 603 impairs, while those at positions 612/613 enhance the CRAF kinase activity. However, the underlying mechanistic details by which these mutations increase or decrease kinase activity remain elusive. Therefore, we applied molecular dynamic simulation to investigate the impacts of these point mutations on the conformation of the CRAF kinase domain. The results revealed that the substitution of Leucine 603 for proline transits the kinase domain to a state that exhibits the molecular hallmarks of an inactive kinase, for example, a closed activation loop, ‘αC-helix out’ conformation and a distorted regulatory hydrophobic spine. However, two HCM-associated variants (S612T and L613V) show features of an active conformation, such as an open activation loop conformation, ‘αC-helix in’, the assembly of the hydrophobic spine, and more surface-exposed catalytic residues of phosphoryl transfer reaction. Overall, our study provides a mechanistic basis for the contradictory effects of the CRAF variants associated with HCM and DCM. Communicated by Ramaswamy H. Sarma