Browsing by Author "Paul, Lucas"

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Computational analysis of Urolithin A as a potential compound for anti-inflammatory, antioxidant, and neurodegenerative pathways
(Elsevier, 2025-02-01) Massaga, Caroline; Paul, Lucas; Kwiyukwa, Lucas; Vianney, John-Mary; Chacha, Musa; Raymond, Jofrey
Urolithin A, an active precursor derived from the metabolism of ellagitanins in rats and humans, is known for its potential health benefits, including stimulating mitophagy and promoting muscular skeletal function. While experimental studies have demonstrated Urolithin A's potential to enhance cellular health, the detailed molecular interactions through which Urolithin A exerts its effects are not fully elucidated. In this study, we investigated the anti-inflammatory, antioxidation and neuroprotective abilities of Urolithin A in selected targets using molecular docking and molecular dynamics simulation methods. Molecular docking studies revealed the strong affinity for receptors involved in inflammation activities, including human p38 MAP kinase (4DLI) with −10.1 kcal/mol interacting with SER252, LYS249, and ASP294 residues. The binding energy in the 5KIR target was −8.6 kcal/mol, interacting with GLN203 through hydrogen bond, and lastly, 1A9U with an affinity of −6.8 with no hydrogen bond formed with Urolithin A and interacts with van der Waals interactions. In oxidant targets, the influence of Urolithin was observed in 1OG5 with −7.9 kcal/mol interacting with GLN185, PHE447. For the 1M17 target, the binding affinity was −7.7 kcal/mol interacting with THR95 residue and 1ZXM target at −7.4 kcal/mol interacting with TYR36, TYR216, and LEU234 residues. The neuroprotective ability of urolithin A was observed in selected targets for acetylcholinesterase; the binding energy was −9.7 kcal/mol interacting with van der Waals and π interactions; for the 1GQR target, the binding energy was −9.9 kcal/mol interacting with van der Waals and π interactions and for β-amylase (1iyt) the binding energy was −5.5 forming hydrogen bond with SER8, GLN15 residues. Molecular Dynamics simulations at 100 ns of Urolithin A compared with reference 4DLI. The Urolithin A-4DLI complex exhibited greater stability than the reference receptor, as confirmed by RMSD, RMSF, Radius of Gyration, Hydrogen bond, and SASA analyses.
A computer-based approach for developing linamarase inhibitory agents
(Walter de Gruyter GmbH, 2020-04-18) Paul, Lucas; Mudogo, Celestin; Mtei, Kelvin; Machunda, Revocatus; Ntie-Kang, Fidele
Cassava is a strategic crop, especially for developing countries. However, the presence of cyanogenic compounds in cassava products limits the proper nutrients utilization. Due to the poor availability of structure discovery and elucidation in the Protein Data Bank is limiting the full understanding of the enzyme, how to inhibit it and applications in different fields. There is a need to solve the three-dimensional structure (3-D) of linamarase from cassava. The structural elucidation will allow the development of a competitive inhibitor and various industrial applications of the enzyme. The goal of this review is to summarize and present the available 3-D modeling structure of linamarase enzyme using different computational strategies. This approach could help in determining the structure of linamarase and later guide the structure elucidation in silico and experimentally
In Silico Analysis of Vitamin D Interactions with Aging Proteins: Docking, Molecular Dynamics, and Solvation Free Energy Studies
(MDPI, 2024-10-11) Tuntufye, Edna; Paul, Lucas; Raymond, Jofrey; Chacha, Musa; Paluch, Andrew; Shadrack, Daniel
Aging is a natural process that is also influenced by some factors like the food someone eats, lifestyle decisions, and impacts on general health. Despite the recognized role of nutrition in modulating the molecular and cellular mechanisms underlying aging, there is a lack of comprehensive exploration into potential interventions that can effectively mitigate these effects. In this study, we investigated the potential anti-aging properties of vitamin D by examining its interactions with key molecular targets involved in aging-related pathways. By using molecular docking and dynamics techniques, we evaluate the interactions and stability of vitamins D2 and D3 with key proteins involved in aging pathways, such as SIRT1, mTOR, AMPK, Klotho, AhR, and MAPK. Our results reveal promising binding affinities between vitamin D and SIRT1 forms, with energy values of −48.33 kJ/mol and −45.94 kJ/mol for vitamins D2 and D3, respectively, in aqueous environments. Moreover, molecular dynamics simulations revealed that the vitamin D3–SIRT1 complex exhibited greater stability compared with the vitamin D2–SIRT1 complex. The study calculated the solvation free energy to compare the solubility of vitamins D2 and D3 in water and various organic solvents. Despite their strong interactions with water, both vitamins exhibited low solubility, primarily due to the high energy cost associated with cavity formation in the aqueous environment. Compared with other solvents, water demonstrated particularly low solubility for both vitamins. This suggested that vitamins D2 and D3 preferred binding to aging receptors over dissolving in bulk aqueous environments, supporting their strong therapeutic interactions with these receptors. These findings shed light on the molecular mechanisms underlying vitamin D’s potential anti-aging effects and lay the groundwork for developing nutraceuticals targeting aging and associated diseases. Understanding these mechanisms holds promise for future interventions aimed at promoting healthy aging and enhancing overall well-being.
A Molecular Investigation of the Solvent Influence on Inter- and Intra-Molecular Hydrogen Bond Interaction of Linamarin
(MDPI, 2022-02-11) Paul, Lucas; Deogratias, Geradius; Shadrack, Daniel; Mudogo, Celestin; Mtei, Kelvin; Machunda, Revocatus; Paluch, Andrew; Ntie‐Kang, Fidele
Linamarin has been reported to have anticancer activities; however, its extraction and isolation using different solvents yield a low amount. Therefore, understanding the physical prop‐ erties, such as solvents’ solubility, membrane permeability and lipophilicity and how they are asso‐ ciated with different solvents, is a paramount topic for discussion, especially for its potential as a drug. Linamarin has a sugar moiety with many polar groups responsible for its physical properties. Following current trends, a molecular dynamics simulation is performed to investigate its physical properties and how different solvents, such as water, methanol (MeOH), dimethyl sulfoxide (DMSO) and dichloromethane (DCM), affect such properties. In this work, we have investigated the influence of intermolecular and intramolecular hydrogen bonding and the influence of polar and non‐polar solvents on the physical properties of linamarin. Furthermore, solvation free‐energy and electronic structure analysis are performed. The structural analysis results show that the polar groups of linamarin have strong interactions with all solvents except the etheric oxygen groups. A detailed analysis shows intermolecular hydrogen bonding between polar solvents (water, MeOH and DMSO) and the hydroxyl oxygens of linamarin. Water exhibits the strongest interaction with linamarin’s functional groups among the investigated solvents. The findings show that within the first solvation shell, the number of water molecules is greatest, while MeOH has the fewest. Cen‐ trally to the structural analysis, solvation free energy confirms DMSO to be the best solvent since it prefers to interact with linamarin over itself, while water prefers to interact with itself. While the solute–solvent interactions are strongest between linamarin and water, the solvent–solvent interac‐ tions are strongest in water. As a result, the solvation free‐energy calculations reveal that linamarin solvation is most favourable in DMSO.
Structural and biophysical characterization of cassava linamarase and the role of solvents on linamarin’s properties: a computational study
(NM-AIST, 2022-06) Paul, Lucas
Linamarase and linamarin mainly from cassava have many applications ranging from food, environmental to the medical industry. To better explore the potential of this enzyme and its substrate, one needs to understand its interaction mechanism at the molecular and atomistic level. In this thesis, the three‒dimensional (3D) structure of linamarase was built via homology modeling. The developed model was used to determine the binding orientation and mechanism of linamarin to the enzyme using molecular docking. Molecular dynamics simulation was used to determine the stability of the built model and when complexed with the ligand. It was interesting to note that complex 1 with the low binding‒free energy of ‒6.9 kcal/mol showed a larger Root Mean Square Deviation (RMSD) value with two maxima at 0.255 and 0.310 nm compared to complex 2 with the best binding‒free energy of ‒7.2 kcal/mol, whose RMSD value shows the maxima at 0.19 nm. The end‒point free energy method based on Molecular Mechanics Poisson Boltzmann Surface Area (MM/PBSA) was used to rescored binding free energy obtained from docking calculations. The ensemble structure was observed to be relatively stable compared to the modelled structure. Furthermore, the stability and conformational orientation preferences of linamarin in different solvents was established using classical molecular dynamics, and found to be solvent dependent. The effects of solvents on the stability and conformational preference is pronounced by different probability density maxima of the measured reaction coordinate/properties. Linamarin is observed to be stable in methanol followed by dimethyl sulfoxide (DMSO) and least stable in water. Solvent polarity was observed to influence the stability and conformation preference of the title compound. Linamarin exists in trans and gauche conformations, the former was observed to be more stable in water than other solvents and the latter in DMSO. The measured reaction coordinates, distance and dihedral angles ascertained that the conformational preference is due to rotation at 𝜙 = ± 180o and 𝜙 = ± 50o . Finally, the stability of linamarin was also attributed to different numbers of inter and intra hydrogen bonds formed in different solvents. Results presented in this thesis provides atomistic insights on the role of solvents polarity on linamarase‒linamarin complex interaction and stability. The findings provide important information on the application of linamarase and linamarin in different fields including food processing and in drugs.
Structural characterization of cassava linamarase-linamarin enzyme complex: an integrated computational approach
(Taylor & Francis Group, 2021-05-21) Paul, Lucas; Shadrack, Daniel; Mudogo, Celestin; Mtei, Kelvin; Machunda, Revocatus; Ntie‐Kang, Fidele
Cassava linamarase is a hydrolyzing enzyme that belongs to a glycoside hydrolase family 1 (GH1). It is responsible for breaking down linamarin to toxic cyanide. The enzyme provides a defensive mechanism for plants against herbivores and has various applications in many fields. Understanding the structure of linamarase at the molecular level is a key to avail its reaction mechanism. In this study, the three-dimensional (3D) structure of linamarase was built for the first time using homology modelling and used to study its interaction with linamarin. Molecular docking calculations established the binding and orientation nature of linamarin, while molecular dynamics (MD) simulation established protein-ligand complexes' stability. Binding-free energy based on MM/PBSA was further used to rescore the docking results. An ensemble structure was found to be relatively stable compared to the modelled structure. This study sheds light on the exploration of linamarase towards understanding its reaction mechanisms.