Computational quest for finding potential Ebola VP40 inhibitors: a molecular docking study

Interaction of Ebola virus matrix protein VP40 with RNA is crucial in the early infection stage to facilitate the transcription of the viral gene. Thus, VP40 is a promising target to inhibit the Ebola virus from spreading. This study aims to identify and optimize ligands that can potentially block the VP40-RNA binding site. A total of 42 compounds from previously studied ligands from the literature were simulated against the RNA binding site using Autodock Vina. The top ten ligands were used as templates for similarity search in ZINC database followed by structured-based virtual screening. Then, the ADME properties of the top compounds were predicted computationally using SwissADME server. Our results showed that Q-96 (ZINC ID: 1338855) is the best docked compound with binding free energy of -7.5 kcal/mol. The compound also has satisfactory ADME properties prediction with good lipophilicity value, moderate water solubility and high gastrointestinal absorption. Besides, this ligand does not violate any drug likeness rules as well as no PAINS and Brenk alerts, indicate it has the properties as a drug. Thus, it is worth to carry out further investigations on this structure more in silico as well as in vitro and in vivo levels towards finding the treatment for Ebola virus disease

CHNS analysis towards food waste in composting

High food waste generation in Malaysia that reached up to 15, 000 tonnes per day assign for major problems towards environment, economy and social aspect. Alternative method had been studied for the past years, but composting was seen among the best possible solution to treat this matter. Composting not only has an environmentally method but it also produces a valuable end product that will benefit in agricultural sector. Further studies had been done in this paper to represent their macro and micro nutrient quality as well as their bioavailability towards plant and the analysis of data collected in both CHNS analyser and mathematical method using ultimate analysis. This study also applied enhanced composting process with its segregation, drying, grinding and standard aeration time. Each container has been rotated for 5 minutes yet different resting time was applied which are 25, 55, 155 minutes namely A, B, C and D within 2 hours period. Result shown that overall Carbon (C), Nitrogen (N) and Sulphur (S) concentration increases as the higher aeration was applied while the Hydrogen vice versa. The highest elemental percentage distribution recorded is carbon (31%) while the lowest recorded is S (0.115%). The data collected from Ultimate Analysis was seen not applicable to be use as it has the same content as food waste after composting. The compound molecular formula recorded was C29H7N5S. Regarding ratio of carbon to nitrogen results, it was found that it ranged from 5.39 to 5.71% for different compost treatment under study, where the lowest value of C and N ratio (5.39%) for sample C and the highest value (5.71%) was obtained for sample B with all has the same C/N ratio which is 6: 1 which suitable range in application of soil amendment. Therefore, this study found a significant relationship between chemical factors and compost formation which contribute to better analysis, especially to food waste management

Computational studies of potential ebola vp40 inhibitors using bioactive compounds from medicinal plants of Malaysia

Ebola virus (EBOV) belongs to Filoviridae family, a deadly virus that can cause severe viral haemorrhagic fevers (VHF) with a high fatality rate between 25 to 90 percent. Amongst EBOV proteins, the EBOV matrix protein VP40 is crucial in facilitating the transcription of the viral gene in the early stage of infection. To date, there is no cure for EBOV and available chemical drugs were known to cause severe side effects. It is known that bioactive compounds from natural products can potentially combat this viral disease with fewer side effects. Therefore, this study aims to screen 15 bioactive compounds of medicinal plants from Malaysia. These compounds were docked against the RNA active site (Phe125 and Arg134) on VP40 matrix protein using AutoDock Vina. The ADMET properties and the toxicity class of the compounds were predicted computationally, and the compounds with good oral bioavailability were chosen for docking simulations. The top three docked compounds namely apigenin, epiexcelsin and kaempferol have a binding affinity of -4.6, -4.4 and -4.3 kJ/mol respectively. Our MD simulation study showed that epiexcelsin is the best candidate among the three selected compounds. Binding free energy calculation via molecular-mechanics Poisson Boltzmann surface area (MM- PBSA) method showed that epiexcelsin has the lowest binding free energy of -56.503 kJ/mol compared to apigenin (-40.344 kJ/mol) and kaemferol (- 27.329 kJ/mol). Our results suggest that epiexcelsin from local herbal plants can potentially be explored as a good candidate for further development of EBOV inhibitor targeting VP40

The discovery of physical properties of food waste in composting process.

Composting as a method of solid waste management should be given attention. It gives means of producing a valuable end product, by treating of organic wastes in an environmentally friendly method which does not release any hazardous chemical which can affect human health without causing a major disruption to the surrounding ecosystem. Nevertheless, the issue of time-consuming arises and this correspond to the sink of market demand. The optimized pre-composting process was done through drying, grinding and controlled aeration resulted in the fast-compost formation and cost-effective. This study aimed to discover the physical properties of food waste in composting process. The controlled parameter of the composting which is aeration time where pre-composting processes applied was drying and grinding. The manipulated parameter of composting process happened within two durations: rotation and rest. Each container has been rotated for 15 minutes yet different resting time was applied which are 15, 25, 50, 150 minutes namely A, B, C and D. The data collection has been done in hourly basis for the total of 72 hours. Based on the statistical analysis, results show that mass reduction of samples (A=38.6%, B=32.6%, C=24.6%, D=22.6%). The compost temperature ranged between (23°C - 39°C) while the compost pH was (5.12 – 5.85). Peak level of surrounding temperature was (35.7°C) while surrounding relative humidity (53%) in normal condition. Among the highest moisture content was (52.63%) while the lowest discovered in sample D (24.81%) respectively. Results show that with the longer the aeration time, the better physical properties of compost formed. The obtained data will provide evidence on its significances application to the agencies, the public and the industrial player to cope up with this major environmental threat. This study found a significant relationship between physical factors and compost formation which contribute to better analysis, especially to food waste management

Computational quest for finding potential Ebola VP40 inhibitors: a molecular docking study = [pencarian pengiraan untuk mencari potensi perencat Ebola VP40: suatu kajian mengedok molekul]

Interaction of Ebola virus matrix protein VP40 with RNA is crucial in the early infection stage to facilitate the transcription of the viral gene. Thus, VP40 is a promising target to inhibit the Ebola virus from spreading. This study aims to identify and optimize ligands that can potentially block the VP40-RNA binding site. A total of 42 compounds from previously studied ligands from the literature were simulated against the RNA binding site using Autodock Vina. The top ten ligands were used as templates for similarity search in ZINC database followed by structured-based virtual screening. Then, the ADME properties of the top compounds were predicted computationally using SwissADME server. Our results showed that Q-96 (ZINC ID: 1338855) is the best docked compound with binding free energy of -7.5 kcal/ mol. The compound also has satisfactory ADME properties prediction with good lipophilicity value, moderate water solubility and high gastrointestinal absorption. Besides, this ligand does not violate any drug likeness rules as well as no PAINS and Brenk alerts, indicate it has the properties as a drug. Thus, it is worth to carry out further investigations on this structure more in silico as well as in vitro and in vivo levels towards finding the treatment for Ebola virus disease. © 2020 Penerbit Universiti Kebangsaan Malaysia

Interaction of monomeric Ebola VP40 protein with a plasma membrane: a coarse-grained molecular dynamics (CGMD) simulation study

Ebola virus is a lipid-enveloped filamentous virus that affects human and non-human primates and consists of several types of protein: nucleoprotein, VP30, VP35, L protein, VP40, VP24, and transmembrane glycoprotein. Among the Ebola virus proteins, its matrix protein VP40 is abundantly expressed during infection and plays a number of critical roles in oligomerization, budding and egress from the host cell. VP40 exists predominantly as a monomer at the inner leaflet of the plasma membrane, and has been suggested to interact with negatively charged lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylserine (PS) via its cationic patch. The hydrophobic loop at the C-terminal domain has also been shown to be important in the interaction between the VP40 and the membrane. However, details of the molecular mechanisms underpinning their interactions are not fully understood. This study aimed at investigating the effects of mutation in the cationic patch and hydrophobic loop on the interaction between the VP40 monomer and the plasma membrane using coarse-grained molecular dynamics simulation (CGMD). Our simulations revealed that the interaction between VP40 and the plasma membrane is mediated by the cationic patch residues. This led to the clustering of PIP2 around the protein in the inner leaflet as a result of interactions between some cationic residues including R52, K127, K221, K224, K225, K256, K270, K274, K275 and K279 and PIP2 lipids via electrostatic interactions. Mutation of the cationic patch or hydrophobic loop amino acids caused the protein to bind at the inner leaflet of the plasma membrane in a different orientation, where no significant clustering of PIP2 was observed around the mutated protein. This study provides basic understanding of the interaction of the VP40 monomer and its mutants with the plasma membrane

In silico study of Thiourea derivatives as potential epidermal growth factor receptor inhibitors

Over the years, the escalation of cancer cases has been linked to the resistance, less selectivity, and toxicity of available anticancer drugs to normal cells. Therefore, continuous efforts are necessary to find new anticancer drugs with high selectivity of epidermal growth factor receptor tyrosine kinase (EGFR-TK) as a therapeutic target. The EGFR-TK protein has a crucial role in cell proliferation and cancer progression. With about 30% of cancer cases involved with the protein, it has piqued the interest as a therapeutic target. The potential of theoretically designed thiourea derivatives as anticancer agents in this report was evaluated against EGFR-TK via in silico techniques, including molecular docking (AutoDock Vina), molecular dynamics simulations (GROMACS), pharmacokinetics, and drug-likeness properties (SwissADME and Molinspiration). New hybrid molecules of the thiourea derivative moiety were designed in this study based on the fragment-based drug discovery and linked with diverse pharmacophoric fragments with reported anticancer potential ( ) and the modification of the methyl position on phenyl ring ( ). These fragments include pyridine, thiophene, furan, pyrrole and styrene groups. Out of 15 compounds, compound 13 displayed the most potent inhibitory activity, with the lowest binding affinity in docking of 8.7 kcal/mol compared to the positive control erlotinib of 6.7 kcal/mol. Our molecular dynamics (MD) simulations revealed that molecule 13, comprising styrene and 2-methylphenyl substituents on and, respectively, showed adequate compactness, uniqueness and satisfactory stability. Subsequently, the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and drug-likeness properties also indicate that this theoretically designed inhibitor ( 13) is less toxic and contains high druggable properties. Thus, compound 13 could be promising against EGFR-TK

The mechanistic role of active site residues in non-stereo haloacid dehalogenase E(DehE)

Dehalogenase E (DehE) is a non-stereospecific enzyme produced by the soil bacterium, Rhizobium sp. RC1. Till now, the catalytic mechanism of DehE remains unclear although several literature concerning its structure and function are available. Since DehE is non-stereospecific, the enzyme was hypothesized to follow a ‘direct attack mechanism’ for the catalytic breakdown of a haloacid. For a molecular insight, the DehE modelled structure was docked in silico with the substrate 2-chloropropionic acid (2CP) in the active site. The ideal position of DehE residues that allowed a direct attack mechanism was then assessed via molecular dynamics (MD) simulation. It was revealed that the essential catalytic water was hydrogen bonded to the ‘water-bearer’, Asn114, at a relatively constant distance of ~2.0 Å after 50 ns. The same water molecule was also closely sited to the catalytic Asp189 at an average distance of ~2.0 Å, signifying the imperative role of the latter to initiate proton abstraction for water activation. This reaction was crucial to promote a direct attack on the a-carbon of 2CP to eject the halide ion. The water molecule was oriented favourably towards the a-carbon of 2CP at an angle of ~75�, mirrored by the formation of stable enzyme-substrate orientations throughout the simulation. The data therefore substantiated that the degradation of a haloacid by DehE followed a ‘direct attack mechanism’. Hence, this study offers valuable information into future advancements in the engineering of haloacid dehalogenases with improved activity and selectivity, as well as functionality in solvents other than water

Homology modeling and docking studies of δ19-fatty acid desaturase from a Cold-tolerant Pseudomonas sp. AMS8

Membrane-bound fatty acid desaturases perform oxygenated desaturation reactions to insert double bonds within fatty acyl chains in regioselective and stereoselective manners. The Δ9-fatty acid desaturase strictly creates the first double bond between C9 and 10 positions of most saturated substrates. As the three-dimensional structures of the bacterial membrane fatty acid desaturases are not available, relevant information about the enzymes are derived from their amino acid sequences, site-directed mutagenesis and domain swapping in similar membrane-bound desaturases. The cold-tolerant Pseudomonas sp. AMS8 was found to produce high amount of monounsaturated fatty acids at low temperature. Subsequently, an active Δ9-fatty acid desaturase was isolated and functionally expressed in Escherichia coli. In this paper we report homology modeling and docking studies of a Δ9-fatty acid desaturase from a Cold-tolerant Pseudomonas sp. AMS8 for the first time to the best of our knowledge. Three dimensional structure of the enzyme was built using MODELLER version 9.18 using a suitable template. The protein model contained the three conserved-histidine residues typical for all membrane-bound desaturase catalytic activity. The structure was subjected to energy minimization and checked for correctness using Ramachandran plots and ERRAT, which showed a good quality model of 91.6 and 65.0%, respectively. The protein model was used to preform MD simulation and docking of palmitic acid using CHARMM36 force field in GROMACS Version 5 and Autodock tool Version 4.2, respectively. The docking simulation with the lowest binding energy, −6.8 kcal/mol had a number of residues in close contact with the docked palmitic acid namely, Ile26, Tyr95, Val179, Gly180, Pro64, Glu203, His34, His206, His71, Arg182, Thr85, Lys98 and His177. Interestingly, among the binding residues are His34, His71 and His206 from the first, second, and third conserved histidine motif, respectively, which constitute the active site of the enzyme. The results obtained are in compliance with the in vivo activity of the Δ9-fatty acid desaturase on the membrane phospholipids

The mechanistic role of active site residues in non-stereo haloacid dehalogenase E(DehE)

Dehalogenase E (DehE) is a non-stereospecific enzyme produced by the soil bacterium, Rhizobium sp. RC1. Till now, the catalytic mechanism of DehE remains unclear although several literature concerning its structure and function are available. Since DehE is non-stereospecific, the enzyme was hypothesized to follow a ‘direct attack mechanism’ for the catalytic breakdown of a haloacid. For a molecular insight, the DehE modelled structure was docked in silico with the substrate 2-chloropropionic acid (2CP) in the active site. The ideal position of DehE residues that allowed a direct attack mechanism was then assessed via molecular dynamics (MD) simulation. It was revealed that the essential catalytic water was hydrogen bonded to the ‘water-bearer’, Asn114, at a relatively constant distance of ~2.0 Å after 50 ns. The same water molecule was also closely sited to the catalytic Asp189 at an average distance of ~2.0 Å, signifying the imperative role of the latter to initiate proton abstraction for water activation. This reaction was crucial to promote a direct attack on the a-carbon of 2CP to eject the halide ion. The water molecule was oriented favourably towards the a-carbon of 2CP at an angle of ~75�, mirrored by the formation of stable enzyme-substrate orientations throughout the simulation. The data therefore substantiated that the degradation of a haloacid by DehE followed a ‘direct attack mechanism’. Hence, this study offers valuable information into future advancements in the engineering of haloacid dehalogenases with improved activity and selectivity, as well as functionality in solvents other than water