Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase ...inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (
), with a docking score of -10.6 kcal⋅mol
, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that
formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound
showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Selecting suitable targets is the critical first step in drug discovery. However, for malaria and dengue this is quite a challenging step due to a large number of available structures for every ...disease targets, about 139 crystal structures for dengue and 367 structures for malaria. This study employed a combination of druggability filtering and computational analysis through molecular docking and molecular dynamics (MD) simulations in oder to select suitable drug targets for dengue and malaria. Initially, diverse target structures for dengue and malaria in Protein Data Bank were assessed for their druggability and as the result, druggable targets were chosen. There were three potential druggable targets NS5, NS3 and NS2B-NS3 protease for dengue, and several targets involved in the food vacuole, apicoplast, mitochondria, cytosol, phosphatidylcholine synthesis pathways for malaria. Molecular docking of co-crystallised ligands with these targets was carried out and the complexes of targets satisfied with high binding affinies and RMSD values were selected. Subsequently, MD simulations of these complexes were run for 100 ns and different conformational structures of target proteins during the period of time were extracted for ensemble docking for each target. Re-docking results showed a significant difference in using equilibrium structures and initial structures from PDB. Finally, the suitable target structures were selected, including NS5 MTase for dengue and plasmepsin for malaria which can be used for further drug design studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Emergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial ...activity against the resistant strains. One of the most promising therapeutic targets of anti-malarial agents related to food vacuole of malaria parasite is haemozoin, a product formed by the parasite through haemoglobin degradation.
Methods
With this in mind, this study developed two-dimensional-quantitative structure–activity relationships (QSAR) models of a series of 21 haemozoin inhibitors to explore the useful physicochemical parameters of the active compounds for estimation of anti-malarial activities. The 2D-QSAR model with good statistical quality using partial least square method was generated after removing the outliers.
Results
Five two-dimensional descriptors of the training set were selected: atom count (a_ICM); adjacency and distance matrix descriptor (GCUT_SLOGP_2: the third GCUT descriptor using atomic contribution to logP); average total charge sum (h_pavgQ) in pKa prediction (pH = 7); a very low negative partial charge, including aromatic carbons which have a heteroatom-substitution in “ortho” position (PEOE_VSA-0) and molecular descriptor (rsynth: estimating the synthesizability of molecules as the fraction of heavy atoms that can be traced back to starting material fragments resulting from retrosynthetic rules), respectively. The model suggests that the anti-malarial activity of haemozoin inhibitors increases with molecules that have higher average total charge sum in pKa prediction (pH = 7). QSAR model also highlights that the descriptor using atomic contribution to logP or the distance matrix descriptor (GCUT_SLOGP_2), and structural component of the molecules, including topological descriptors does make for better anti-malarial activity.
Conclusions
The model is capable of predicting the anti-malarial activities of anti-haemozoin compounds. In addition, the selected molecular descriptors in this QSAR model are helpful in designing more efficient compounds against the P
. falciparum
3D7A strain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With the emergence of antibody-evasive omicron subvariants (BA.2.12.1, BA.4, and BA.5), which can compromise the efficacy of vaccination, it is of utmost importance to widen the finite therapeutic ...options for COVID-19. Although more than 600 co-crystal complexes of Mpro with inhibitors have been revealed, utilizing them to search for novel Mpro inhibitors remains limited. Although there were two major groups of Mpro inhibitors, covalent and noncovalent inhibitors, noncovalent inhibitors were our main focus due to the safety concerns with their covalent counterparts. Hence, this study aimed to explore Mpro noncovalent inhibition ability of phytochemicals extracted from Vietnamese herbals by combining multiple structure-based approaches. By closely inspecting 223 complexes of Mpro with noncovalent inhibitors, a 3D-pharmacophore model representing typical chemical features of Mpro noncovalent inhibitors was generated with good validation scores (sensitivity = 92.11%, specificity = 90.42%, accuracy = 90.65%, and goodness-of-hit score = 0.61). Afterward, the pharmacophore model was applied to explore the potential Mpro inhibitors from our in-house Vietnamese phytochemical database, revealing 18 substances, 5 of which were in vitro assayed. The remaining 13 substances were then examined by induced-fit molecular docking, revealing 12 suitable compounds. A machine-learning activity prediction model was developed to rank the hit, suggesting nigracin and calycosin-7-O-β-glucopyranoside as promising Mpro natural noncovalent inhibitors.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Diabetes mellitus is one of the top ten causes of death worldwide, accounting for 6.7 million deaths in 2021, and is one of the most rapidly growing global health emergencies of this century. ...Although several classes of therapeutic drugs have been invented and applied in clinical practice, diabetes continues to pose a serious and growing threat to public health and places a tremendous burden on those affected and their families. The strategy of reducing carbohydrate digestibility by inhibiting the activities of α-glucosidase and α-amylase is regarded as a promising preventative treatment for type 2 diabetes. In this study, we investigated the dual inhibitory effect against two polysaccharide hydrolytic enzymes of flavonoid derivatives from an in-house chemical database. By combining molecular docking and structure–activity relationship analysis, twelve compounds with docking energies less than or equal to − 8.0 kcal mol
−1
and containing required structural features for dual inhibition of the two enzymes were identified and subjected to chemical synthesis and in vitro evaluation. The obtained results showed that five compounds exhibited dual inhibitory effects on the target enzymes with better IC
50
values than the approved positive control acarbose. Molecular dynamics simulations were performed to elucidate the binding of these flavonoids to the enzymes. The predicted pharmacokinetic and toxicological properties suggest that these compounds are viable for further development as type 2 diabetes drugs.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Despite noticeable improvement in anti-malarial treatment, rapid growth of resistant malaria strains points out the need for continuous development of novel anti-malarials to fight the disastrous ...infection. Haemozoin is considered as a novel inhibitory pathway for new anti-malarial drugs, therefore, this study aimed to systematically review all articles investigating the correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds.
A literature search was conducted on 22 October 2017 in eight databases for relevant in vitro articles reporting the correlation between anti-malarial and anti-haemozoin of anti-malarial compounds, based on the constructed search terms and inclusion criteria. ToxRtool was used to assess quality of each study.
A total of ten articles were included in the review. In vitro anti-malarial and anti-haemozoin activity had a good correlation for quinolines for sensitive strains (R
ranging from 0.66 to 0.95) and xanthones (Spearman ρ = 0.886). However, these correlations were reached after removing some compounds which had non-detectable anti-malarial or anti-haemozoin effects. Other structures (acridines, pyrolidines) showed negligible correlation with Spearman ρ ranging from 0.095 to 0.381 for acridines, and r varying from 0.54 to 0.62 for pyrolidines. Some good correlations were only shown in a logarithmic manner or when the anti-malarial activity was normalized.
The results raised a relative relationship between anti-haemozoin and in vitro anti-malarial activities. Some studies reported compounds that were effective in the inhibition of haemozoin formation, but failed to inhibit the parasite survival and vice versa. The correlation results in these studies were calculated after these compounds were removed from their analysis. The ability of anti-malarial compounds to accumulate inside the reaction site might strengthen their anti-malarial activity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug-coated balloon (DCB) angioplasty has been shown to be a promising option for the treatment of coronary in-stent restenosis (ISR). We compared the clinical outcomes of patients with ISR who were ...treated with two commonly used paclitaxel-containing DCBs, the Pantera Lux (PL) and SeQuent Please (SP). A total of 491 patients with 507 ISR lesions PL-DCB in 127 (26%) patients and SP-DCB in 364 (74%) patients underwent DCB angioplasty for ISR lesions. The major adverse cardiac events (MACEs), including cardiac death, target lesion-related myocardial infarction, and target lesion revascularization, were assessed. There were no significant differences in each occurrence of MACE and cardiac death: 16 MACEs (61 per 1000 person-years) in the PL-DCB group and 55 (60 per 1000 person-years) MACEs in the SP-DCB group, log-rank
p
= 0.895, and three cardiac deaths (11 per 1000 person-years) in the PL-DCB group and ten cardiac deaths (11 per 1000 person-years) in the SP-DCB group, log-rank
p
= 0.849. Diabetes mellitus under insulin treatment hazard ratio (HR) 2.71; 95% confidence interval (CI) 1.31–5.60;
p
= 0.007, chronic kidney disease (HR 1.99; 95% CI 1.01–3.92;
p
= 0.045), early-onset ISR (HR 1.99; 95% CI 1.18–3.36;
p
= 0.010), and recurrent ISR (HR 1.89; 95% CI 1.08–3.32;
p
= 0.026) were associated with the occurrence of MACE after DCB angioplasty. There was no significant difference of MACE between PL-DCB and SP-DCB treatment in patients with ISR. Patients with insulin-treated diabetes, chronic kidney disease, early-onset ISR, and recurrent ISR were at a higher risk of MACE after DCB angioplasty.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although the atheroprotective effects of statins and angiotensin II receptor blockers (ARBs) are well-established, little is known about their additive effects, especially during the early period of ...atherosclerosis. The aim of this study was to investigate whether combination of a statin and an ARB exerts synergistic anti-atherosclerotic effects, and to elucidate the mechanisms of combined effects.
Atherosclerotic plaques were developed in arteries of 23 rabbits using a high-cholesterol diet (HCD) and intra-arterial balloon inflation. Rabbits received one of five different treatment strategies for 4 weeks: positive control n = 5, HCD; negative control n = 3, regular chow diet; statin n = 5, HCD and rosuvastatin 10 mg; ARB n = 5, HCD and olmesartan 20 mg; and combination n = 5, HCD and statin+ARB.
Histological analysis demonstrated that development of atherosclerotic plaques was inhibited more in combination group than in statin group (P = 0.001). Although macrophage infiltration identified by RAM11 staining was not significantly different between combination and individual treatment groups (31.76±4.84% combination vs. 38.11±6.53% statin; P = 0.35 or 35.14±2.87% ARB; P = 0.62), the relative proportion of pro-inflammatory M1-macrophages was significantly lower in combination group than in ARB group (3.20±0.47% vs. 5.20±0.78%, P = 0.02). Furthermore, M2-macrophage polarization was higher in combination group than in statin group (17.70±3.04% vs. 7.86±0.68%, P = 0.001).
Combination treatment with a statin and an ARB produced synergistic protective effects for atherosclerosis initiation and progression, which may be attributed to modulation of macrophage characteristics in the early period of atherosclerosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The global water crisis is being exacerbated by climate change, even in the United States. Recycled water is a feasible alternative to alleviate the water shortage, but it is constrained by humans’ ...perceptions. The current study examines how residents’ water scarcity awareness and climate change belief influence their willingness to use recycled water directly and indirectly. Bayesian Mindsponge Framework (BMF) analytics was employed on a dataset of 1831 residents in Albuquerque, New Mexico, an arid inland region in the US. We discovered that residents’ willingness to use direct recycled potable water is positively affected by their awareness of water scarcity, but the effect is conditional on their belief in the impacts of climate change on the water cycle. Meanwhile, the willingness to use indirect recycled potable water is influenced by water scarcity awareness, and the belief in climate change further enhances this effect. These findings implicate that fighting climate change denialism and informing the public of the water scarcity situation in the region can contribute to the effectiveness and sustainability of long-term water conservation and climate change alleviation efforts.
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