Browsing by Author "Dahanayake, J. N."

Now showing 1 - 9 of 9

Computational assessment of novel derivatives of epigallocatechin gallate as potential anti-Alzheimer agents
(Faculty of Science, University of Kelaniya Sri Lanka, 2022) Rajapaksha, R. P. G. A. P.; Dahanayake, J. N.
Alzheimer's disease (AD) is a chronic, neurodegenerative disease that affects memory, thinking, and behaviour problems. The neuroprotective effects of natural products against AD have been studied in preclinical and clinical studies using in vitro and in vivo models. This computational chemistry study explores the effects of epigallocatechin gallate (EGCG) and its novel derivatives as potential anti-Alzheimer agents using computational chemistry. Among natural products that are tested against AD in clinical studies, catechins are a very commonly found constituent of green tea. Catechins are a bioactive ingredient of green tea and potential anti-oxidative and anti-inflammatory agents. In addition, various putative features associated with AD prevention and modification have been discovered in preclinical in vitro and in vivo studies of catechins. Due to its anti-inflammatory and antioxidant properties, EGCG has neuroprotective effects on AD patients’ brains. EGCG inhibits the formation of neurotoxic beta-amyloid and regulates the formation of a soluble form of amyloid protein (sAPP) and prevents AD progression. Effects of EGCG and its derivatives on Amyloid precursor protein (APP), Amyloid β-protein (Aβ), Alzheimer's Beta A fibrils (Aβ - fibrils), Acetylcholine esterase (AChE), Butyryl choline esterase (BChE), and Tau protein were investigated in this study. Those proteins are highly associated with AD. The Density Functional Theory (DFT) calculations were used to get energy-optimised structures of EGCG and derivative EGCG-G1, EGCG-G2, PEGCG, EGCG-EPA, 5,3,4,3,4,5-O-ethyl-EGCG, and (-)/ (+)-epicatechin-3-O-gallate. The binding interaction of those ligands with each protein can be understood by molecular docking studies. To compare protein-ligand interactions, the protein-donepezil complex was used as a reference in molecular docking. Donepezil is a clinically approved drug for AD. Among considered ligands, EGCG, PEGCG, and (-)/ (+)-epicatechin-3-O-gallate showed better docking scores with AChE, BChE, and APP proteins. Those protein-ligand complexes that showed the best docking scores and protein-donepezil complexes were taken to further analysis of Molecular Dynamics simulations (MD). MD simulations were done for a 50 ns period on protein-ligand complexes which are selected according to docking scores. In MD simulations, CHARMM36 forcefield was used for protein. For ligands, external sources were used for generating topology. The parameters that were used for MD analysis to determine the stability of protein-ligand complexes were Radius of gyration (Rg), Root Mean Square Deviation (RMSD), and Root Mean Square Fluctuation (RMSF). The MD analysis, along with docking studies, revealed that the EGCG and derivative PEGCG can act as anti-Alzheimer agents due to their effects on important AD-related proteins.
Computational assessment of novel derivatives of Epigallocatechin gallate as potential anti-Tuberculosis agents
(Faculty of Science, University of Kelaniya Sri Lanka, 2023) Perera, K. P. M.; Dahanayake, J. N.
Tuberculosis (TB) is a highly contagious bacterial infection caused by Mycobacterium tuberculosis. This research focuses on the computational assessment of novel derivatives of Epigallocatechin Gallate (EGCG) as potential anti-TB agents. Through the utilization of molecular docking studies using AutoDock 4.2 and molecular dynamics (MD) simulations employing GROMACS, this study aims to explore the therapeutic potential of these EGCG derivatives. Specific molecular targets associated with TB, including Pantothenate kinase, UDPN- acetylmuramoyl-l-alanyl-d-glutamate-2,6-diaminopimelate ligase, 3-oxoacy-(Acyl-carrierprotien) reductase, Decaprenylphosphoryl-β-D-ribose oxidase, Dihydrofolate reductase, Enoyl- [acyl-carrier-protein] reductase (NADH) were selected for investigation. Bedaquiline, an approved tuberculosis medication, was utilized as a benchmark molecule for validation purposes. By conducting molecular docking studies, strong binding affinities were observed between certain EGCG derivatives and the targeted tuberculosis proteins. To gain insights into the stability, dynamic behaviour, and conformational changes, MD simulations were performed using GROMACS, which allowed for extended-time observations of the EGCG derivatives within the binding pockets of the TB targets. Evaluation of stability parameters, such as root mean square deviation (RMSD) and root mean square fluctuation (RMSF) complemented the docking results, providing a comprehensive understanding of the binding modes and stability of the EGCG derivatives. Furthermore, the calculation of binding free energies using advanced scoring functions from AutoDock facilitated the estimation of binding affinities, thus aiding in the assessment of relative potency and selectivity of the derivatives towards the TB targets. The reference drug Bedaquiline, known for its effectiveness against TB, was also included in the comparative analysis. In conclusion, this computational study highlights the promising potential of EGCG derivatives as long-term control medications for TB. The integration of molecular docking, MD simulations, binding free energy calculations, and interaction studies provided valuable insights into the binding affinity, stability, selectivity, and delivery optimization of these derivatives. These findings significantly contribute to the field of computational drug discovery and pave the way for future experimental investigations and optimization of EGCG derivatives as highly effective long-term control medications for tuberculosis.
Computational assessment of novel derivatives of gingerol as potential anti Alzheimer agents
(Faculty of Science, University of Kelaniya Sri Lanka, 2022) Disanayaka, D. M. I. M.; Dahanayake, J. N.
Ginger (Zingiber officinale) is commonly used as a spice and folk medicine, which helps to prevent heart diseases, high blood pressure and lung diseases. Gingerols, zingiberene, shogaols and monoterpenes are the principal components of the extract of ginger. Gingerol is known to provide protective effects against Alzheimer’s disease (AD). AD is a neurodegenerative disease, resulting in loss of cognitive activity and memory and impaired signalling among brain cells. There are only a few approved drugs available for AD. Since developing synthetic chemicals as drugs is a challenging task, many pharmaceutical companies are now focused on the development of plant-derived drugs. Therefore, discovering natural products with medicinal properties for AD as lead compounds can be considered as an important task. There are five main proteins involved in AD: Amyloid precursor protein (APP), Tau protein, Amyloid β-protein (Aβ), Alzheimer's Beta A fibrils (Aβ - fibrils) and Acetylcholine esterase (AChE). In this study, the effects of 6-gingerol eight gingerol derivatives on those five main proteins highly associated with AD were considered to investigate anti-Alzheimer activities. Donepezil which is commonly used as a clinical drug in Alzheimer was considered as a reference compound. Initially, energy minimized structures of 6-gingerol, and its derivatives were obtained using molecular mechanical calculations. Docking studies were carried out for the 6-gingerol and suggested derivatives with AD related proteins. Through docking studies, secondary interactions with target proteins and amino acid residues in binding pockets were identified. The binding affinities of derivatives with proteins were compared with the binding affinity of the parent molecule (6-gingerol). According to the results, the parent molecule and studied derivatives have good binding affinities with Acetylcholinesterase. Therefore, further studies of molecular dynamic (MD) simulation studies were performed for the Acetylcholinesterase-ligand complexes for 50 ns using the CHARMM36 force field. The trajectories obtained from MD simulations were used to calculate the radius of gyration (Rg), root mean square deviation (RMSD) and root mean square fluctuation (RMSF). According to the Rg and RMSD results, the studied protein-ligand complexes were stable throughout the simulation time. Further, RMSF results of derivatives were compared with the results of 6-gingerol parent molecule, in order to investigate the higher binding affinities of the derivatives. The stability of the complexes is an essential feature which can provide information about the lifetime of the complex. Therefore, the ligand bound to the proteins can act as an inhibitor and inhibit the specific function of that protein. Since Rg and RMSD results showed the stability of the protein-ligand complexes, it can be stated that the studied gingerol derivatives have the ability to inhibit AChE. Therefore, the MD analysis results, along with docking results, indicated that the studied gingerol derivatives have the potential to act as promising anti-Alzheimer agents.
Computational investigation of novel Curcumin derivatives as anti -Tuberculosis Agents
(Faculty of Science, University of Kelaniya Sri Lanka, 2023) Amarasena, M. W. K. A.; Dahanayake, J. N.
Tuberculosis (TB) remains a major global health burden, necessitating the development of novel and effective anti-TB drugs. Curcumin a naturally occurring compound found in turmeric has shown potential as an antimicrobial agent, including activity against Mycobacterium tuberculosis the causative agent of TB. In this computational study, the potential of natural derivatives of curcumin as anti-TB drugs was investigated using molecular docking studies and molecular dynamics (MD) simulations. Bedaquiline was used as the reference drug. Using Auto Dock 4.2, molecular docking studies were performed to predict the binding affinities and binding modes of a library of curcumin derivatives with the selected TB targets. The outcomes of the molecular docking studies showed that numerous curcumin derivatives have high affinity for the targeted proteins: Decaprenylphosphoryl-β-D-ribose oxidase protein, Dihydrofolate reductase protein, Enoyl- {acyl-carrier protein} reductase (NADH) protein, InhA 4,3-oxoacyl-(Acyl-carrierprotein) reductase protein, Pantothenatekinaseprotein, UDP-N-Acetylmuramoyl-L-Alanyl-DGlutamate-2,6 Diaminopimelateligase protein. Insights into prospective curcumin derivatives' modes of action as long-term control drugs were offered by the docking scores and interaction profiles. The key interactions influencing the binding process were also understood by investigation of the binding modes. The stability and dynamic behaviour of the chosen curcumin derivatives in complex with the TB targets were examined using MD simulations. These simulations allowed for the long-term study of conformational changes, flexibility, and stability of the derivatives of curcumin within the binding pockets of TB targets. Understanding the dynamic behaviour and interactions of the curcumin derivatives with TB targets was made possible by MD simulations. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) are two metrics used to assess stability. The results of the docking were supplemented by information from the MD simulations, providing a thorough insight into the binding modes and stability of the curcumin derivatives. By estimating binding affinities through the use of Auto Dock's advanced scoring methods, it was possible to calculate binding free energies and it revealed that all derivatives except one have good binding affinities with the studied proteins. It helped to reveal that the studied natural derivatives clarify the relative potency and selectivity of the derivatives for the tuberculosis targets. In conclusion, the computational findings of this study suggest that natural derivatives of curcumin hold promise as anti-TB drugs. These findings provide a basis for further experimental investigations and optimization of the identified curcumin derivatives as potential candidates for the development of novel anti-TB drugs.
Computational investigation of the effect of natural derivatives of Curcumin as anti-Asthma drugs
(Faculty of Science, University of Kelaniya Sri Lanka, 2023) Abeyrathne, N. G. D. S.; Dahanayake, J. N.
Asthma, a chronic respiratory disease, necessitates long-term control medications to manage symptoms and maintain stable control. However, the search for novel therapeutics with improved efficacy and reduced side effects remains ongoing. This computational study focused on exploring the potential of curcumin derivatives as long-term control medications for asthma. Key molecular targets implicated in asthma pathogenesis, Interleukin-4, Interleukin-13, Nuclear factor kappa B (NF-κB), Tumor necrosis factor-alpha (TNF-α), Signal transducer and activator of transcription 6 (STAT6), Phosphoinositide 3-kinase (PI3K), Transforming growth factor-beta (TGF-β), Peroxisome proliferator-activated receptor gamma (PPAR-γ) and Cyclooxygenase-2 (COX-2), were selected for investigation. A library of Curcumin derivatives was designed, and molecular docking experiments were conducted using Auto Dock 4.2 to predict the binding affinity and binding modes of the derivatives with the selected asthma targets. Montelukast was used as the reference drug, which is a medication commonly used in the long-term control of asthma and the management of seasonal allergies. The results of the molecular docking revealed strong binding affinities of several curcumin derivatives towards the targeted asthma proteins: Nitro-curcumin, Cyclo-curcumin, and Desmethoxycurcumin (DMC). The docking scores and interaction profiles provided insights into the potential mechanisms of action of the curcumin derivatives as longterm control medications. Additionally, analysis of the binding modes offered understanding regarding the key interactions driving the binding process. Molecular dynamics (MD) simulations were performed to investigate the stability and dynamic behaviour of the selected curcumin derivatives in complex with the asthma targets. These simulations enabled the observation of conformational changes, flexibility, and stability of the curcumin derivatives within the binding pockets of the asthma targets over extended time scales. Evaluation of stability was conducted using parameters such as root mean square deviation (RMSD) and root mean square fluctuation (RMSF). The information gained from MD simulations complemented the docking results, offering a comprehensive understanding of the binding modes and stability of the curcumin derivatives. Calculating binding free energies using advanced scoring functions provided by Auto Dock allowed the estimation of binding affinities, aiding in understanding the relative potency and selectivity of the derivatives towards the asthma targets. In conclusion, this computational study demonstrated the potential of curcumin derivatives as long-term control medications for asthma. This computational investigation has allowed for further experimental investigations and optimization of curcumin derivatives as effective long-term control medications for asthma.
Computational studies of derivatives of selected marine organisms on acute myeloid leukemia
(Faculty of Science, University of Kelaniya Sri Lanka, 2023) Deemantha, N. A. H. W. S.; Dahanayake, J. N.
Acute myeloid leukemia (AML) is the most common subtype of leukemia cancer that produces an uncontrolled number of muted blood cells in the bone marrow. AML is common among adults, and it affects red blood cells, white blood cells and platelets. The anticancer activity of marine organisms has been proven in several in vitro and in vivo preclinical and clinical studies. Amongst several Marine ecosystems, Marine sponges are the richest source of anticancer compounds, because they are endowed with natural compounds that can act against AML by targeting active protein sites. This study highlights the investigation of binding interaction between the natural Marine derivatives and the proteins associated with AML and comparing the values with a reference drug using a computational chemistry platform. The natural Marine derivatives which are selected for the present study are lacking information about the drug potency against AML. The main proteins that are targets for this study are Receptor tyrosine kinase (C-Kit), FMS-like tyrosine kinase 3 (FLT3), Myeloid leukemia (MCL1), Glycogen synthase kinase (GSK3), Casein kinase 2 (CK2), while the derivatives of Marine sponges are Gracillin J, Gracillin K, Gracillin L and 3-norspongio. ARA-which is also known as Cytarabine is a Food and Drug Administration (FDA) approved drug for chemotherapy and it was used as a reference drug for this research. A molecular docking study was conducted to determine the binding energies of the interaction of selected proteins and ligand using Auto Dock 4.2 software in which the derivatives of Marine sponge’s act as ligands for the active binding sites of proteins associated with AML. Further, Root Mean Square Deviation (RMSD) was calculated for the protein-ligand complexes to discover the stability of the protein-ligand complexes. The computational studies revealed that the natural derivatives of Marine sponges have the potential to act against the AML cancer cells due to the relatively high binding energies compared to that of ARA-C drug.
In-silico insights of effects of major phytoconstituents in pomegranate on prostate cancer
(Faculty of Science, University of Kelaniya Sri Lanka, 2024) Kariyawasam, K. B. G. A. S.; Dahanayake, J. N.
Among diverse cancer types, prostate cancer is the second most common non-cutaneous cancer type in males. Various treatment options at present target AR (Androgen Receptor) signaling cascade, EGFR (Epidermal Growth Factor Receptor) inhibition, and PI3k signal transduction mechanism. The ultimate medications for prostate cancer are xenobiotics which show diverse side effects on the human body. Consequently, scientists’ approach is to develop new medications derived from phytoconstituents originating from different plant species. In Ayurvedic and traditional medication practices, it was believed that phytoconstituents present in pomegranate (Punica granatum) have antioxidant, antiinflammatory, and anti-tumor properties. In this research, the agonistic, antagonistic, and inhibitory nature of polyphenols and flavones present in pomegranate were investigated and compared with reference drugs that are commercially available to ascertain the results. The in-silico study assessed the effectiveness of major seven secondary metabolites present in pomegranate (catechin, citric acid, ellagic acid, ellagic acid-4-O-xylopyranoside, gallic acid, quercitrin, and vanillic acid) against AR and EGFR. The geometry-optimized molecules were docked using Autodock 4.2.6 with their respective protein targets. The scoring functions of docking were utilized to determine free binding energies and inhibition constants. To enhance a better understanding, two-dimensional and three-dimensional aspects of interactions and the interacting residues were visualized by Discovery Studio software. The natural ligands: testosterone and xenobiotics (Bicalutamide, Enzalutamide, Gefitinib and Erlotinib) were used as reference compounds. The results indicated that binding free energies for AR were between -5 to - 12 kcal/mol and for EGFR -3 to -7 kcal/mol. The lowest Inhibition constant values (Ki) were in the nanomolar range for AR and in the micromolar range for EGFR. The lowest binding energies for AR ranged as testosterone (-11.78 kcal/mol) < ellagic acid-4-O-xylopyranoside (-8.76 kcal/mol) < catechin (-8.57 kcal/mol) < bicalutamide (-8.33 kcal/mol) < ellagic acid (-8.12 kcal/mol) < enzalutamide (-7.96 kcal/mol) in ascending order. The lowest binding energies for EGFR ranged as gefitinib (-6.61 kcal/mol) < catechin (-5.98 kcal/mol) < ellagic acid (-5.51 kcal/mol) < ellagic acid-4-O-xylopyranoside (-5.18 kcal/mol) < erlontib (-4.75 kcal/mol) in ascending order. It was evident that the potential of ellagic acid-4-O-xylopyranoside, ellagic acid, and catechin compounds to act as a kind of novel inhibitor and an insight into the designing of structurally novel potent anti-carcinogenic which will be more economical and beneficial in the pharmaceutical industry.
Molecular docking studies of phytochemicals of pomegranate as anti-breast cancer agents
(Faculty of Science, University of Kelaniya Sri Lanka, 2024) Sathyajith, G. K. Y.; Dahanayake, J. N.
Breast cancer is second most common cancer type in the world amd scientists have been moving towards natural phytochemicals as an anti-cancer agent because most anti-cancer drugs affect other healthy cells. One such natural source is pomegranate (Punica granatum). It contains several phytochemicals: namely, ellagic acid, ellagic acid-4-O-xylopyranoside, gallic acid, vanillic acid, (+)- catechin, quercitrin, and citric acid. Recent research studies have pointed out that these polyphenols posses strong anti-cancer activity through a variety of mechanisms. Molecular docking of phytochemicals against breast cancer can provide insights not only about these different mechaisms, but also about structural features required to improve inhibitory activities. Therefore, this study has focused on the computational analysis of selected phytochemicals that affect the transforming growth factor receptor (TGFBR) (1KSQ) and estrogen receptor (ER-α) (2IOG). Blind docking was performed and the binding free energies and Inhibition constants (Ki) were calculated. Higher binding free energies have shown for (+)-catechin and ellagic acid-4-O-xylopyranoside with TGFBR (-7.17 kcal/mol and - 7.38 kcal/mol respectively) and (+)-catechin, ellagic acid and ellagic acid-4-O-xylopyranoside with ER- α receptor (-7.84 kcal/mol, -7.26 kcal/mol and -8.82 kcal/mol respectively). Quercitrin has observed moderate binding free energy for both TGFBR (-6.58 kcal/mol) and ER-α receptor (-6.68 kcal/mol). Other phytochemicals like citric acid, gallic acid, and vanillic acid have observed relatively low binding free energies for both receptors. The binding affinities of pomegranate phytochemicals were compared with reference binding ligands (TGF-β for TGFBR and Estradiol for ER-α receptor) and present anticancer drug tamoxifen. According to the results, Ellagic acid-4-O-xylopyranoside has a lower inhibition constant than the other phytochemicals and it has higher inhibition for receptor-ligand complex. Therefore, it can be suggested that pomegranate contains an anti-breast cancer effect and the most effective phytochemical is Ellagic acid-4-O-xylopyranoside. Ellagic acid-4-O-xylopyranoside has shown greater binding affinity and lower inhibition constant for both receptors than the ellagic acid. Therefore, formation of derivatives of pomegranate phytochemicals can be more effective than the natural source. This study reveals that several pomegranate phytochemicals have been shown positive effects on cancer therapy. These findings will be further confirmed through molecular dynamics (MD) simulation studies.
Natural plant products as potential Cyclooxygenase-2 (COX-2) inhibitors: An insilico drug discovery study
(Faculty of Science, University of Kelaniya Sri Lanka, 2023) Dissanayaka, I. G. G. S.; Dahanayake, J. N.
Natural plant products have gained widespread recognition for their medicinal properties and have been used in traditional medicine for centuries. In recent years, there has been an increase in interest in exploring natural plant products as a potential source of new drug candidates for various diseases, particularly inflammation-related conditions. Cyclooxygenase-2 (COX-2) is a crucial enzyme involved in inflammation and is considered as a prime target for the development of anti-inflammatory drugs. In this study, we employed computational methods to investigate the potential of selected natural plant products as COX-2 inhibitors. A comprehensive screening of a database of natural plant products was conducted using molecular docking and molecular dynamics (MD) simulation techniques to identify potential COX-2 inhibitors. Molecular docking is a computational approach that predicts the binding affinity of ligand molecules to a target protein, while molecular dynamics is a computational simulation method used to study the behaviour and movement of molecules over time. Docking studies were carried out using a crystal structure of COX-2 as the receptor, and the binding free energies of the docked compounds were calculated. The results revealed that the selected natural plant products exhibited promising binding affinities to COX-2, suggesting their potential as COX-2 inhibitors. The binding energies in kilocalories per mole (kcal/mol) of the five ligands with the COX-2 protein can be arranged in descending order as; Tubulosine (-9.82), Dicentrine (-9.34), Celecoxib (-9.02), Crebanine (-8.87), and Cycleanine (-8.10), with 3,5'-dihydroxythalifaboramine exhibiting a binding energy of -7.38 kcal/mol. MD simulations were performed on protein-ligand complexes for 50 ns using CHARMM36 force field and the mean radius of gyration (Rg), root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. The results of MD simulation analysis indicated the stability of the protein-ligand complex throughout the simulation time. These studied compounds belonged to diverse classes of natural products, including terpenoids, alkaloids, and phenolic compounds, which are known for their anti-inflammatory properties. Additionally, some of the identified compounds exhibited binding affinities to COX-2 that were comparable to or even better than known COX-2 inhibitors such as celecoxib, a selective COX-2 inhibitor, which is a currently prescribed drug for inflammation-related conditions. The MD analysis results along with docking results highlights the potential of natural plant products as a valuable source of COX-2 inhibitors, which could serve as a starting point for further experimental investigations and the development of novel anti-inflammatory drugs. The findings of this study contribute to the significance of natural plant products in drug discovery and provide insights into their potential as promising candidates for the treatment of inflammation-related diseases.