The potential of some functional group compounds substituted 8-Manzamine A as RSK1 inhibitors: molecular docking and molecular dynamics simulations.

Cancer, an incurable global disease, demands urgent anti-cancer drug development. Marine alkaloids like Manzamine and its derivatives show promise as RSK inhibitors against cancer cell invasion. Replacing the hydrogen at the 8-position of Manzamine A with a hydroxyl group has been shown to significantly enhance its biological activity. In this article, we designed various functional group compounds (A1-A21) substituted 8-Manzamine A by docking, MM-GBSA, molecular dynamics (MD) simulation, and well-tempered metadynamics (WT-MetaD) simulations to evaluate their potential as RSK1 inhibitors. Ligands A1-A21 were docked in the RSK1 N-terminal kinase domain (PDB ID: 2Z7Q) using the Glide module. The calculation of binding energy was performed using Prime MM-GB/SA, while MD simulations were conducted with the Desmond module of Schrodinger suite 2023. Compound A5 exhibits the highest G-score (-7.01) compared to 8-Hydroxymanzamine A (-6.08). Additionally, compounds A6, A10, A12, A17, A11, A4, and A13 demonstrate increased activity against RSK1 when compared to both 8-Hydroxymanzamine A and Manzamine A. Residues LEU68, VAL76, LEU141, PHE143, LEU144, PHE150, ASP148, GLU191, and LEU194 of RSK1 protein play a key role in binding with ligands. An MD simulation of Compound A5 was carried out to explore the dynamic interactions within the protein-ligand complex. Furthermore, WT-MetaD simulations validated the docking study results and identified the most energetically favored conformations for the A5/RSK1 complex. Ligands A5, A6, A10, A12, A17, A11, A4, and A13, featuring diverse functional groups and good Glide scores, may have the potential for significant RSK1 activity and merit further development.Communicated by Ramaswamy H. Sarma.

Functional group modifications at the 8-position of Manzamine A enhance its inhibitory activity against RSK1.Amine and carbonyl groups at position 8 of Manzamine A enhance its inhibitory activity, especially when accompanied by an aryl group.This research lays a solid groundwork for future drug development targeting RSK1, offering promising candidates for further investigation.

Cation-stimulated drug delivery via lipid assembly comprising macrocyclized disaccharides - A DFT study.

In the attempt to create a delivery system for an alkali-cation stimulated drug release, a computational study was conducted, aiming for the evaluation of synthetic access towards glycolipid crown ethers analogs and their potential for coordination-induced changes of packing constraints for molecular assemblies. The results disfavor amide-linkages for the creation of macrocycles around the inter-glycosidic bond of a disaccharide. Conformational changes upon cation coordination of the macrocycle decrease the intersection area for easily accessible macrocycles based on lactose. This leads to shrinking intersection areas upon alkali complexation. Maltose-based analogs, on the other hand, exhibited the targeted increase of the glycolipid intersection area and, hence, may be considered as a promising resource.

Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins-designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2-DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala → Asp and Ser → Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions.

Support vector machines for oil classification link with polyaromatic hydrocarbon contamination in the environment.

The main focus of this study is exploring the spatial distribution of polyaromatics hydrocarbon links between oil spills in the environment via Support Vector Machines based on Kernel-Radial Basis Function (RBF) approach for high precision classification of oil spill type from its sample fingerprinting in Peninsular Malaysia. The results show the highest concentrations of Σ Alkylated PAHs and Σ EPA PAHs in ΣTAH concentration in diesel from the oil samples PP3_liquid and GP6_Jetty achieving 100% classification output, corresponding to coherent decision boundary and projective subspace estimation. The high dimensional nature of this approach has led to the existence of a perfect separability of the oil type classification from four clustered oil type components; i.e diesel, bunker C, Mixture Oil (MO), lube oil and Waste Oil (WO) with the slack variables of ξ ≠ 0. Of the four clusters, only the SVs of two are correctly predicted, namely diesel and MO. The kernel-RBF approach provides efficient and reliable oil sample classification, enabling the oil classification to be optimally performed within a relatively short period of execution and a faster dataset classification where the slack variables ξ are non-zero.

Daily exposure to toxic metals through urban road dust from industrial, commercial, heavy traffic, and residential areas in Petaling Jaya, Malaysia: a health risk assessment.

Human health is threatened by significant emissions of heavy metals into the urban environment due to various activities. Various studies describing health risk analyses on soil and dust have been conducted previously. However, there are limited studies that have been carried out regarding the potential health risk assessment of heavy metals in urban road dust of < 63-µm diameter, via incidental ingestion, dermal contact, and inhalation exposure routes by children and adults in developing countries. Therefore, this study evaluated the health risks of heavy metal exposure via ingestion, dermal contact, and inhalation of urban dust particles in Petaling Jaya, Malaysia. Heavy metals such as lead (Pb), chromium (Cr), zinc (Zn), copper (Cu), and manganese (Mn) were measured using dust samples obtained from industrial, high-traffic, commercial, and residential areas by using inductively coupled plasma mass spectrometry (ICP-MS). The principal component and hierarchical cluster analysis showed the dominance of these metal concentrations at sites associated with anthropogenic activities. This was suggestive of industrial, traffic emissions, atmospheric depositions, and wind as the significant contributors towards urban dust contamination in the study sites. Further exploratory analysis underlined Cr, Pb, Cu, and Zn as the most representative metals in the dust samples. In accommodating the uncertainties associated with health risk calculations and simulating the reasonable maximum exposure of these metals, the related health risks were estimated at the 75th and 95th percentiles. Furthermore, assessing the exposure to carcinogenic and non-carcinogenic metals in the dust revealed that ingestion was the primary route of consumption. Children who ingested dust particles in Petaling Jaya could be more vulnerable to carcinogenic and non-carcinogenic risks, but the exposure for both children and adults showed no potential health effects. Therefore, this study serves as an important premise for a review and reformation of the existing environmental quality standards for human health safety.

Correlation between polar surface area and bioferroelectricity in DNA and RNA nucleobases.

We have performed computational molecular modelling to study the polarization switching and hysteresis loop behaviours of DNA and RNA nucleobases using the PM3 semi-empirical quantum mechanical approaches. All the nucleobases: adenine (A), thymine (T), guanine (G), cytosine (C), and uracil (U) were modelled. Our study indicates that all the nucleobases exhibit a zero-field polarization due to the presence of polar atoms or molecules such as amidogen and carbonyl. The shape of polarization P versus an applied electric field E hysteresis loop is square, implying typical ferroelectrics behaviour. The total energy U as a function of an applied electric field E exhibits a butterfly-like loop. The presence of zero-field polarization and ferroelectrics hysteresis loop behaviours in nucleobases may support the hypothesis of the existence of bioferroelectricity in DNA and RNA. We also found an interesting relationship between the minimum electric field required for switching [Formula: see text] and the ratio of the topological polar surface area (TPSA) to the total surface area (TSA) of a nucleobase. In particular, the [Formula: see text] of a nucleobase is inversely proportional to the TPSA/TSA ratio. This work may provide useful information for understanding the possible existence of ferroelectricity in biomaterials.

Study of Cationic and Nonionic Mixed Micelles with NaBr and 3,5-Cl2C6H3CO2Na by Use of Probe Nucleophilic Reaction of Piperidine with Ionized Phenyl Salicylate.

Behaviors of cationic and nonionic mixed micelles in the form of hexadecyltrimethylammonium bromide (HDABr) and hexadecyltrimethylammonium bromide-Polyethylene glycol hexadecyl ether (C16E20), in the presence of inert salts (NaBr and 3,5-dichlorosodium benzoate), by the use of reaction probe between Pp and ionized PhSH (Pp = piperidine and PhSH = phenyl salicylate), has been reported in this work. The values of RXBr (RXBr denotes ion exchange constants obtained in the presence of micelles of different structural features) or KXBr (KXBr denotes ion exchange constants obtained in the presence of micelles of the same structural features) for 3,5-Cl2C6H3CO2- were almost the same at three different [HDABr]T (0.006, 0.010 and 0.015 M). The average value of RXBr or KXBr determined, in the presence of pure HDABr micelles, using semi empirical kinetic (SEK) method appeared to be almost 2½-fold larger (RXBr or KXBr = 198) than that in the presence of mixed HDABr-C16E20 micelles (RXBr or KXBr = 78). Rheological measurements indicated the existence of wormlike/twisted micelles and vesicle at 0.015 M pure HDABr, various [3,5-Cl2C6H3CO2Na], and 25 and 35℃ whereas there were evidence of only spherical micelles in the presence of mixed HDABr-C16E20 ([HDABr]T = 0.015 M and [C16E20]T = 0.006 M) at both temperatures.

Consumption of water from ex-mining ponds in Klang Valley and Melaka, Malaysia: A health risk study.

Evaluation of health risks due to heavy metals exposure via drinking water from ex-mining ponds in Klang Valley and Melaka has been conducted. Measurements of As, Cd, Pb, Mn, Fe, Na, Mg, Ca, and dissolved oxygen, pH, electrical conductivity, total dissolved solid, ammoniacal nitrogen, total suspended solid, biological oxygen demand were collected from 12 ex-mining ponds and 9 non-ex-mining lakes. Exploratory analysis identified As, Cd, and Pb as the most representative water quality parameters in the studied areas. The metal exposures were simulated using Monte Carlo methods and the associated health risks were estimated at 95th and 99th percentile. The results revealed that As was the major risk factor which might have originated from the previous mining activity. For Klang Valley, adults that ingested water from those ponds are at both non-carcinogenic and carcinogenic risks, while children are vulnerable to non-carcinogenic risk; for Melaka, only children are vulnerable to As complications. However, dermal exposure showed no potential health consequences on both adult and children groups.

Improving oil classification quality from oil spill fingerprint beyond six sigma approach.

This study involves the use of quality engineering in oil spill classification based on oil spill fingerprinting from GC-FID and GC-MS employing the six-sigma approach. The oil spills are recovered from various water areas of Peninsular Malaysia and Sabah (East Malaysia). The study approach used six sigma methodologies that effectively serve as the problem solving in oil classification extracted from the complex mixtures of oil spilled dataset. The analysis of six sigma link with the quality engineering improved the organizational performance to achieve its objectivity of the environmental forensics. The study reveals that oil spills are discriminated into four groups' viz. diesel, hydrocarbon fuel oil (HFO), mixture oil lubricant and fuel oil (MOLFO) and waste oil (WO) according to the similarity of the intrinsic chemical properties. Through the validation, it confirmed that four discriminant component, diesel, hydrocarbon fuel oil (HFO), mixture oil lubricant and fuel oil (MOLFO) and waste oil (WO) dominate the oil types with a total variance of 99.51% with ANOVA giving Fstat>Fcritical at 95% confidence level and a Chi Square goodness test of 74.87. Results obtained from this study reveals that by employing six-sigma approach in a data-driven problem such as in the case of oil spill classification, good decision making can be expedited.

H emibagrus sp. as a potential bioindicator of hazardous metal pollution in Selangor River.

The spatial distributions of Na, Mg, K, Ca, Cr, Fe, Ni, Cu, Zn, As, Se and Pb in Hemibagrus sp. from Selangor River and a reference site were determined with inductively coupled plasma-mass spectrometer, in comparison to the levels in their surrounding water body and sediments. The results demonstrated significant differences in elemental accumulation pattern in different fish tissues originated from both sites. The variations observed were mainly subjected to their metabolic activities, and also the influence of the surrounding medium. In general, the liver tends to accumulate higher concentration of metals followed by the gills, and muscle tissues. The data also indicate associations between the concentrations of metal contaminants measured in the fish and the levels observed at the sites. The concentrations of hazardous metals As, Se and Pb in all the studied tissues reflect the influence of anthropogenic inputs. This suggests the potential utility of widely available Hemibagrus sp. as a valuable bioindicator of metal pollution in environmental monitoring and assessment.

Determination of Relative Counterion Binding Constant to Cationic Micelles.

The efficiency of counterion affinity towards ionic micelles is often described in terms of the degree of counterion binding (ß X ) to ionic micelles or the conventional ion-exchange constant ([Formula: see text]) or relative binding constant ([Formula: see text]) of X - and Br- counterions. This review describes the use of ionized phenyl salicylate ions, PSa-, as a new probe to determine [Formula: see text] values using a semiempirical spectrophotometric method. The value of [Formula: see text] is found to be comparable to reported values obtained using different probes by the semiempirical kinetic method as well as different physical methods. Application of semiempirical methods for calculation of [Formula: see text] or [Formula: see text] values involves an inherent assumption that these values are independent of the physicochemical characteristics of the probe molecule.

Isotopic ratio analysis of cattle tail hair: A potential tool in building the database for cow milk geographical traceability.

The potential for the isotopic ratio analysis of cattle tail hair in determining the geographical origin of raw cow milk in Peninsular Malaysia had been investigated in this research using exploratory visualization. A significant positive correlation (p<0.0001) (n=54) was noticed between δ(13)C and δ(15)N in milk with that of hair which indicated that these matrices could be used in tracing the geographical origin of animal produce and tissues, and there is a possibility that hair could be used as a substitute in building the database for the geographical traceability of milk. It was also observed that both hair and milk isotopic ratio correlations exhibited separation between the northern and southern regions. The accuracy of using isotopic ratio in determining geographical discrimination had been clearly demonstrated when several commercial milk samples from the same regions under the study were correctly assigned to the appropriate geographical clusters.

A simple design for microwave assisted digestion vessel with low reagent consumption suitable for food and environmental samples.

The objective of this work is to prepare a cost-effective, low reagent consumption and high performance polytetrafluoroethylene (PTFE) vessel that is capable to work in domestic microwave for digesting food and environmental samples. The designed vessel has a relatively thicker wall compared to that of commercial vessels. In this design, eight vessels are placed in an acrylonitrile butadiene styrene (ABS) holder to keep them safe and stable. This vessel needs only 2.0 mL of HNO3 and 1.0 mL H2O2 to digest 100 mg of biological sample. The performance of this design is then evaluated with an ICP-MS instrument in the analysis of the several NIST standard reference material of milk 1849a, rice flour 1568b, spinach leave 1570a and Peach Leaves 1547 in a domestic microwave oven with inverter technology. Outstanding agreement to (SRM) values are observed by using the suggested power to time microwave program, which simulates the reflux action occurring in this closed vessel. Taking into account the high cost of commercial microwave vessels and the volume of chemicals needed for various experiments (8-10 mL), this simple vessel is cost effective and suitable for digesting food and environmental samples.

Chemometric techniques in oil classification from oil spill fingerprinting.

Extended use of GC-FID and GC-MS in oil spill fingerprinting and matching is significantly important for oil classification from the oil spill sources collected from various areas of Peninsular Malaysia and Sabah (East Malaysia). Oil spill fingerprinting from GC-FID and GC-MS coupled with chemometric techniques (discriminant analysis and principal component analysis) is used as a diagnostic tool to classify the types of oil polluting the water. Clustering and discrimination of oil spill compounds in the water from the actual site of oil spill events are divided into four groups viz. diesel, Heavy Fuel Oil (HFO), Mixture Oil containing Light Fuel Oil (MOLFO) and Waste Oil (WO) according to the similarity of their intrinsic chemical properties. Principal component analysis (PCA) demonstrates that diesel, HFO, MOLFO and WO are types of oil or oil products from complex oil mixtures with a total variance of 85.34% and are identified with various anthropogenic activities related to either intentional releasing of oil or accidental discharge of oil into the environment. Our results show that the use of chemometric techniques is significant in providing independent validation for classifying the types of spilled oil in the investigation of oil spill pollution in Malaysia. This, in consequence would result in cost and time saving in identification of the oil spill sources.

Spatial assessment and source identification of heavy metals pollution in surface water using several chemometric techniques.

This study presents the determination of the spatial variation and source identification of heavy metal pollution in surface water along the Straits of Malacca using several chemometric techniques. Clustering and discrimination of heavy metal compounds in surface water into two groups (northern and southern regions) are observed according to level of concentrations via the application of chemometric techniques. Principal component analysis (PCA) demonstrates that Cu and Cr dominate the source apportionment in northern region with a total variance of 57.62% and is identified with mining and shipping activities. These are the major contamination contributors in the Straits. Land-based pollution originating from vehicular emission with a total variance of 59.43% is attributed to the high level of Pb concentration in the southern region. The results revealed that one state representing each cluster (northern and southern regions) is significant as the main location for investigating heavy metal concentration in the Straits of Malacca which would save monitoring cost and time. CAPSULE: The monitoring of spatial variation and source of heavy metals pollution at the northern and southern regions of the Straits of Malacca, Malaysia, using chemometric analysis.

Antimicrobial Activity of Novel Synthetic Peptides Derived from Indolicidin and Ranalexin against Streptococcus pneumoniae.

Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics in order to defeat multidrug-resistant bacteria such as Streptococcus pneumoniae. In this study, thirteen antimicrobial peptides were designed based on two natural peptides indolicidin and ranalexin. Our results revealed that four hybrid peptides RN7-IN10, RN7-IN9, RN7-IN8, and RN7-IN6 possess potent antibacterial activity against 30 pneumococcal clinical isolates (MIC 7.81-15.62µg/ml). These four hybrid peptides also showed broad spectrum antibacterial activity (7.81µg/ml) against S. aureus, methicillin resistant S. aureus (MRSA), and E. coli. Furthermore, the time killing assay results showed that the hybrid peptides were able to eliminate S. pneumoniae within less than one hour which is faster than the standard drugs erythromycin and ceftriaxone. The cytotoxic effects of peptides were tested against human erythrocytes, WRL-68 normal liver cell line, and NL-20 normal lung cell line. The results revealed that none of the thirteen peptides have cytotoxic or hemolytic effects at their MIC values. The in silico molecular docking study was carried out to investigate the binding properties of peptides with three pneumococcal virulent targets by Autodock Vina. RN7IN6 showed a strong affinity to target proteins; autolysin, pneumolysin, and pneumococcal surface protein A (PspA) based on rigid docking studies. Our results suggest that the hybrid peptides could be suitable candidates for antibacterial drug development.

Distribution and health risk assessment of trace metals in freshwater tilapia from three different aquaculture sites in Jelebu Region (Malaysia).

The trace metal concentrations in edible muscle of red tilapia (Oreochromis spp.) sampled from a former tin mining pool, concrete tank and earthen pond in Jelebu were analysed with microwave assisted digestion-inductively coupled plasma-mass spectrometry. Results were compared with established legal limits and the daily ingestion exposures simulated using the Monte Carlo algorithm for potential health risks. Among the metals investigated, arsenic was found to be the key contaminant, which may have arisen from the use of formulated feeding pellets. Although the risks of toxicity associated with consumption of red tilapia from the sites investigated were found to be within the tolerable range, the preliminary probabilistic estimation of As cancer risk shows that the 95th percentile risk level surpassed the benchmark level of 10(-5). In general, the probabilistic health risks associated with ingestion of red tilapia can be ranked as follows: former tin mining pool > concrete tank > earthen pond.

Computational evaluation of unsaturated carbonitriles as neutral receptor model for beryllium(II) recognition.

Design of neutral receptor molecules (ionophores) for beryllium(II) using unsaturated carbonitrile models has been carried out via density functional theory, G3, and G4 calculations. The first part of this work focuses on gas phase binding energies between beryllium(II) and 2-cyano butadiene (2-CN BD), 3-cyano propene (3-CN P), and simpler models with two separate fragments; acrylonitrile and ethylene. Interactions between beryllium(II) and cyano nitrogen and terminal olefin in the models have been examined in terms of geometrical changes, distribution of charge over the entire π-system, and rehybridization of vinyl carbon orbitals. NMR shieldings and vibrational frequencies probed charge centers and strength of interactions. The six-membered cyclic complexes have planar structures with the rehybridized carbon slightly out of plane (16° in 2-CN BD). G3 results show that in 2-CN BD complex participation of vinyl carbon further stabilizes the cyclic adduct by 16.3 kcal mol(-1), whereas, in simpler models, interaction between beryllium(II) and acetonitrile is favorable by 46.4 kcal mol(-1) compared with that of ethylene. The terminal vinyl carbon in 2-CN BD rehybridizes to sp (3) with an increase of 7 % of s character to allow interaction with beryllium(II). G4 calculations show that the Be(II) and 2-CN BD complex is more strongly bound than those with Mg(II) and Ca(II) by 98.5 and 139.2 kcal mol(-1) (-1), respectively. QST2 method shows that the cyclic and acyclic forms of Be(II)-2-CN BD complexes are separated by 12.3 kcal mol(-1) barrier height. Overlap population analysis reveals that Ca(II) can be discriminated based on its tendency to form ionic interaction with the receptor models.

Rational design of carbonitrile-carboxaldehyde cation receptor models: probing the nature of the heteroatom-metal interaction.

In this work, hybrid functional and G4 methods were employed in the rational design of carbonitrile-carboxaldehyde receptor models for cation recognition. Electron-sharing and ionic interactions between the models and the cations were analyzed utilizing the concepts of overlap population, atomic valence, electrostatic potential, and CHELPG charge in order to elucidate the nature of the heteroatom-metal interaction, the N versus O disparity, and the effect of pH. Receptor fragment models from ionomycin were employed to rationalize the selection of receptor models for discriminating group I cations and enhancing the selectivity for Mg(II) rather than Ca(II), and to examine the effects of keto-enol forms and negatively charged sites. The changes in geometries, overlap population, metal valence, and CHELPG charge upon solvation in heptane medium as compared to the gas phase were negligible. The optimized geometries reveal that the interaction between group II cations and the keto, enol, and enolate forms of 2-cyanoethanal causes 12 % bending of the C-C-N angle from linearity. Overlap populations show that the electron-sharing interaction favors group II cations but that the same mechanism allows Li(I) to compete. The total spin of Li(I) is 17 % greater than that of Ca(II), but the G4 binding energies of the two are separated by more than 50 kcal/mol, favoring group II cations, which may eliminate interference from Li(I). 1,2-Dicyanoethylene, which has only one form, shows similar characteristics. CHELPG analysis shows that Mg(II) transfers 25 and 18 % of its positive charge to 2-cyanoethanal enolate and 1,2-dicyanoethylene, respectively. Hydrogen atoms receive most of the positive charge in both receptors, but the N-termini exhibit strikingly different characteristics. Electrostatic potential contour profiles were found to be in good agreement with the atomic charge distributions. The application of uncharged 1,3-dicarbonyl and 2-cyanocarbonyl receptors and a judicious choice of polymeric membrane that suppresses the Hofmeister effect should lead to high selectivity for magnesium, whereas the utilization of multiple negatively charged ionophores should result in selectivity for calcium.