Molecular Modeling Techniques Research Articles

WITHDRAWN: Revealing the neuroprotection and neurodegeneration efficacy of marine sponge extract in Parkinson's disease using gene expression and molecular docking

Parkinson's disease is one of the most prevalent neurological conditions (PD). The pathogenesis of PD was thought to involve mitochondrial dysfunction and oxidative stress. In this study, PD was induced in zebrafish models, and the effectiveness of MS01 sponge extract in neuroprotective effects was assessed. In zebrafish models, rotenone and MS01-mixed pellets were fed, tested for sensitivity and motor function, and euthanized. Histopathology and confocal images of the zebrafish brain were then analyzed for the expression of the PINK1 and Parkin genes. Gene expression study showed MS01 was effective against neurodegeneration at a dose-dependent concentration. The compound xenin identified by LC-MS/MS analysis was selected for in silico studies. Using molecular docking and modeling techniques, the gene expression of PINK1 and Parkin were also investigated. The analysis showed binding of the xenin peptide to the PINK1-Ubiquitin complex may enhance the stability of the complex and increase the production of Parkin, which reduces Parkinson's disease symptoms (PD). This demonstrates the neuroprotective effects of the xenin peptide.

Interactions between carbon nanotubes and external structures of SARS-CoV-2 using molecular docking and molecular dynamics

Molecular modeling techniques are used to describe the process of interaction between nanotubes and the main structures of the Covid-19 virus: the envelope protein, the main protease, and the Spike glycoprotein. Molecular docking studies show that the ligands have interaction characteristics capable of adsorbing the structures. Molecular dynamics simulations provide information on the mean squared deviation of atomic positions ​​between 0.5 and 3.0 Å. The Gibbs free energy model and solvent accessible surface area approaches are used. Through the results obtained through molecular dynamics simulations, it is noted that the zig-zag nanotube prefers to interact with E-pro, M-pro, and S-gly, respectively. Molecular couplings and free energy showed that the S-gly active site residues strongly interact with zigzag, chiral, and armchair nanotubes, in this order. The interactions demonstrated in this manuscript may predict some promising candidates for virus antagonists, which may be confirmed through experimental approaches.

Design, synthesis and biological evaluation of novel thiosemicarbazones as cruzipain inhibitors

Based on the activity of 23 TSCs on CZ taken from the literature, we have developed a QSAR model for predicting the activity of TSCs. New TSCs were designed and then tested against CZP, resulting in inhibitors with IC50 values in the nanomolar range. The modelling of the corresponding TSC-CZ complexes by molecular docking and QM/QM ONIOM refinement indicates a binding mode compatible with what was expected for active TSCs, according to a geometry-based theoretical model previously developed by our research group. Kinetic experiments on CZP suggest that the new TSCs act by a mechanism that involves the formation of a reversible covalent adduct with slow association and dissociation kinetics. These results demonstrate the strong inhibitory effect of the new TSCs and the benefit of the combined use of QSAR and molecular modelling techniques in the design of new and potent CZ/CZP inhibitors.

Recent Theoretical Insights into the Oxidative Degradation of Biopolymers and Plastics by Metalloenzymes.

Molecular modeling techniques have become indispensable in many fields of molecular sciences in which the details related to mechanisms and reactivity need to be studied at an atomistic level. This review article provides a collection of computational modeling works on a topic of enormous interest and urgent relevance: the properties of metalloenzymes involved in the degradation and valorization of natural biopolymers and synthetic plastics on the basis of both circular biofuel production and bioremediation strategies. In particular, we will focus on lytic polysaccharide monooxygenase, laccases, and various heme peroxidases involved in the processing of polysaccharides, lignins, rubbers, and some synthetic polymers. Special attention will be dedicated to the interaction between these enzymes and their substrate studied at different levels of theory, starting from classical molecular docking and molecular dynamics techniques up to techniques based on quantum chemistry.

Molecular structure, spectral, computational, IEFPCM investigation, and topological study on the biologically potent; cardiotonic drug 2-chloroquinolin-3-amine with structural optimization

The current study provides a detailed DFT analysis of the drug 2-Chloroquinolin-3-amine, which has biological potential as a cardiotonic (2CQ3A). The molecular structure is theoretically optimised using DFT with the basis set B3LYP/6–311++G(d,p), and parameters were measured .Potential energy distribution was used in Fourier transforms, IR, and Raman analysis. Different solvents underwent UV–Visible analysis, and the bandgap energy of the Frontier molecular orbital were compared. By using NBO and MEP studies in various solvents, the molecule's stability and reactivity were predicted using the IEFPCM methodology. The compound's non-linear optical behavior is demonstrated by NLO analysis in a variety of polar and non-polar solvents. AIM, ELF, LOL, and RDG were predicted by topological analysis. ADME properties and toxicity values are assigned to demonstrate the compound's biological activity. Cardiotonic activity by docking is analysed using molecular modeling techniques.

Computational Strategies for Entropy Modeling in Chemical Processes.

Computational simulations of entropy are important in understanding the thermodynamic forces that drive chemical reactions on a molecular scale. In recent years, various algorithms have been developed and applied in conjunction with molecular modeling techniques to evaluate the change of entropy in solvation, hydrophobic interactions, and chemical reactions. The aim of this review is to highlight four specific computational entropy calculation methods: normal mode analysis, free volume theory, two-phase thermodynamics, and configurational entropy modeling. The technical aspects, applications, and limitations of each method will be discussed in detail.

Interaction of Odoroside A, A Known Natural Cardiac Glycoside, with Na+/K+-ATPase.

The nature of odoroside A, a cardiac glycoside (CG) extracted from Nerium oleander, as well as its chemical structure is quite similar to a well-known CG, ouabain possessing a steroid skeleton, a five-membered unsaturated lactone ring, and a sugar moiety as a common structure. Like ouabain, odoroside A inhibits the activity of Na+/K+-ATPase (NKA) and shows significant anticancer activity, however its inhibitory mechanism remains unknown. CGs show various physiological activities, including cardiotonic and anticancer activities, through the inhibition of NKA by direct interaction. Additionally, X-ray crystallographic analysis revealed the inhibitory mechanism of ouabain and digoxin in relation to NKA. By using different molecular modeling techniques, docking simulation of odoroside A and NKA was conducted based on the results of these X-ray crystallographic analyses. Furthermore, a comparison of the results with the binding characteristics of three known CGs (ouabain, digoxin, and digitoxin) was also conducted. Odoroside A fitted into the CG binding pocket on the α-subunit of NKA revealed by X-ray crystallography. It had key interactions with Thr797 and Phe783. Also, three known CGs showed similar interactions with Thr797 and Phe783. Interaction modes of odoroside A were quite similar to those of ouabain, digoxin, and digitoxin. Docking simulations indicated that the sugar moiety enhanced the interaction between NKA and CGs, but did not show enhanced NKA inhibitory activity because the sugar moiety was placed outside the entrance of active site. Thus, these results suggest that the inhibitory mechanism of odoroside A to NKA is the same as the known CGs.

Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques

A series of pyrrolidine derivatives have been used to study the main structural requirements for designing novel Mcl-1 inhibitors. For this purpose, three models CoMSIA, CoMFA and HQSAR were generated using QSAR molecular modeling techniques. The statistical results of the CoMFA (Q2 = 0.689; R = 0.999; R2pred = 0.986), CoMSIA (Q2 = 0.614; R2 = 0.923; R2pred = 0.815) and HQSAR (Q2= 0.603; R2 = 0.662; R2pred = 0.743) models showed good stability and predictability. The results of the models were presented as contours and colored fragments indicating the favorable and unfavorable contribution to the inhibitory activity of Mcl-1. Based on the obtained results, four new compounds were designed with more potent predicted pIC50 inhibitory activity. The ADME/Tox results and the pharmacokinetic properties revealed that these four compounds are orally bioavailable and show good permeability. In addition the four compounds showing non-inhibitors of CYP3A4 and CYP2D6 with the exception of Pred03. At the level of toxicity profile, the compounds Pred01, Pred02 and Pred03 showed interesting results and showed no AMES toxicity, no hERG inhibition and no skin sensitization. Molecular docking results were used to uncover the mode of interaction between the ligand and key residues of protein binding site. Molecular docking results were supported by molecular simulation and binding free energy estimation (MMPBSA). These results demonstrate the stability of the analyzed compounds in the target protein binding site during a 100 ns trajectory. Finally, all these results create a strong lead to develop promising new Pyrrolidine-based inhibitors against Mcl-1.Communicated by Ramaswamy H. Sarma

Novel phytochemical inhibitors targeting monkeypox virus thymidine and serine/threonine kinase: integrating computational modeling and molecular dynamics simulation

Due to the rapid spread of the monkeypox virus and rise in the number of cases, there is an urgent need for the development of effective drugs against the infection. Serine/threonine protein kinase (Ser/Thr kinase) and Thymidine Kinase (TK) plays an imperative role in the replication and virulence of monkeypox virus and thus is deliberated as an attractive target in anti-viral drug development. In the present study, the 3D structure of monkeypox virus Ser/Thr kinase and TK was generated via molecular modeling techniques and performed their thorough structural analysis. We have screened potent anti-viral phytochemicals from the literature to inhibit Ser/Thr kinase and TK. As part of the initial screening, the physicochemical properties of the compounds were examined. Following this, a structure-based molecular docking technique was used to select compounds based on their binding affinity towards Ser/Thr kinase and TK. In order to find more potent hits against Ser/Thr kinase and TK, further examinations of ADMET properties, PAINS patterns and blood–brain barrier permeability were conducted. As a result, thalimonine and galanthamine were identified from the screening process bearing appreciable binding affinity towards Ser/Thr kinase and TK respectively, which showed a worthy set of drug-like properties. In the end, molecular dynamics simulations were performed for 100 ns, which showed decent stability of both protein–ligand complex throughout the trajectory. Due to the possibility that both monkeypox virus target proteins may be inhibited by thalimonine and galanthamine, our study highlights the need to investigate in vivo effects of thalimonine and galanthamine.Communicated by Ramaswamy H. Sarma

Impact of pH on the interaction between soy whey protein and gum arabic at oil–water interface: Structural, emulsifying, and rheological properties

In this study, gum arabic (GA) and pH modulation were used to change the structural and emulsion properties of soy whey protein (SWP). The interaction mode and binding site of SWP and GA were analyzed by structural characterization and molecular modeling techniques. The microscopic morphological, emulsifying, interfacial, and rheological properties of emulsions formed by SWP–GA complexes were characterized. The ζ-potential results showed that pH has a significant effect on the electrostatic interaction between SWP and GA. Fluorescence spectra and surface hydrophobicity (H0) illustrated that the H0 of SWP–GA complexes significantly decreased. Fourier transform infrared spectroscopy (FTIR) showed that GA provided the basis for the formation of ordered structures and that the β-sheet content of SWP–GA complexes reached the maximum value (44.68%) at pH 6.0. Molecular docking results further verified that SWP–GA interaction occurred through hydrogen bond and hydrophobic interaction. Compared with SWP emulsions, droplets of SWP–GA emulsions were uniformly distributed and formed a dense network structure. The emulsifying activity index and emulsifying stability index significantly improved, especially at pH 6.0, which were 902.78 ± 4.44 m2/g and 4648.27 ± 203.59%, respectively. SWP–GA complexes facilitated adsorption at the oil–water interface and reduced the interfacial tension. GA significantly improved the rheological properties of SWP–GA emulsion. Furthermore, statistical analysis indicated that the structural properties of SWP–GA complexes were significantly correlated with the emulsifying and interfacial properties of SWP–GA emulsions. This study would provide theoretical guidance for the preparation of the stable emulsion system of protein–polysaccharide complexes.

QSAR, ADME-Tox, molecular docking and molecular dynamics simulations of novel selective glycine transporter type 1 inhibitors with memory enhancing properties

A structural class of forty glycine transporter type 1 (GlyT1) inhibitors, was examined using molecular modeling techniques. The quantitative structure-activity relationships (QSAR) technology confirmed that human GlyT1 activity is strongly and significantly affected by constitutional, geometrical, physicochemical and topological descriptors. ADME-Tox in-silico pharmacokinetics revealed that L28 and L30 ligands were predicted as non-toxic inhibitors with a good ADME profile and the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicated that the predicted inhibitors block GlyT1, reacting specifically with Phe319, Phe325, Tyr123, Tyr 124, Arg52, Asp475, Ala117, Ala479, Ile116 and Ile483 amino acids of the dopamine transporter (DAT) membrane protein. These results were qualified and strengthened using molecular dynamics (MD) study, which affirmed that the established intermolecular interactions for (L28, L30–DAT protein) complexes remain perfectly stable along 50 ns of MD simulation time. Therefore, they could be strongly recommended as therapeutics in medicine to improve memory performance.

QSAR study of tetrahydropteridin derivatives as polo-like kinase 1(PLK1) Inhibitors with molecular docking and dynamics study

ABSTRACT PLK1 is the key target for dealing with different cancer because it plays an important role in cell proliferation. According to the regulation of OECD, a QSAR model was developed from a dataset of 68 tetrahydropteridin derivatives. Three descriptors (maxHaaCH, ATSC7i, AATS7m) were considered for the development of the QSAR model. The reliability and predictability of the developed QSAR model were evaluated by various statistical parameters (r 2 = 0.8213, r 2 ext = 0.8771 and CCCext = 0.9364). The maxHaaCH descriptor is positively correlated to pIC50 whereas, the ATSC7i and AATS7m are negatively correlated with pIC50. The QSAR model explains all the structural features and shows a good correlation with the activity. Based on molecular modelling techniques, five compounds (D1-D5) were designed. Molecular docking and dynamics studies of the most active compound were performed with PDB ID: 2RKU. The results of the present investigation may be employed to identify and develop effective inhibitors for the treatment of PLK1-related pathophysiological disorders.

A rational approach to selective targeting of skeletal myosin.

Altered actin-myosin binding in the sarcomere has been linked to congenital skeletal and cardiac myopathies characterised by muscular weakness.1Since the discovery of omecamtiv mecarbil (OM)2, the direct targeting of the myosin II motor protein has been considered as a promising strategy to restore normal muscle function. While there has been success in the development of cardiac myosin drugs, with one of them recently achieving FDA approval,3 selective targeting of skeletal myosin has been less explored. Here, we used a range of molecular modelling techniques to compare the structure and dynamics of the OM binding site in cardiac and in fast type IIa skeletal myosin.4 We found important differences in the shape and size of the binding pocket in the two isoforms, which we relate to small but significant differences in its amino acidic composition. Moreover, inclusion of protein dynamics turned out to be essential to explain the observed selectivity of OM for the cardiac isoform. Information from our modelling is currently being used to identify novel compounds that can selectively bind skeletal myosin, and potentially treat congenital myopathies where muscle weakness is related to myosin loss-of-function.

Molecular dynamics simulations reveal the effect of mutations in the RING domains of BRCA1-BARD1 complex and its relevance to the prognosis of breast cancer

The N-terminal RING-RING domain of BRCA1-BARD1 is an E3 ubiquitin ligase complex that plays a critical role in tumor suppression through DNA double stranded repair mechanism. Mutations in the BRCA1-BARD1 heterodimer RING domains were found to have an association with breast and ovarian cancer by a way of hampering the E3 ubiquitin ligase activity. Herein, the molecular mechanism of interaction, conformational change due to the specific mutations on the BRCA1-BARD1 complex at atomic level has been examined by employing molecular modeling techniques. Sixteen mutations have been selected for the study. Molecular dynamics simulation results reveal that the mutant complexes have more local perturbation with a high residual fluctuation in the zinc binding sites and central helix. A few of the BRCA1 (V11A, I21V, I42V, R71G, I31M and L51W) mutants have been experimentally identified that do not impair E3 ligase activity, display an enhanced number of H-bonds and non-bonded contacts at the interacting interface as revealed by MD simulation. The mutation of BRCA1 (C61G, C64Y, C39Y and C24R) and BARD1 (C53W, C71Y and C83R) zinc binding residues displayed a smaller number of significant H-bonds, other interactions and also loss of some of the hotspot residues. Additionally, most of the mutant complexes display relatively lower electrostatic energy, H-bonding and total stabilizing energy as compared to wild-type. The current study attempts to unravel the role of BRCA1-BARD1 mutations and delineates the structural and conformational dynamics in the progression of breast cancer. Communicated by Ramaswamy H. Sarma

Outstanding anti-corrosion performance of two pyrazole derivatives on carbon steel in acidic medium: Experimental and quantum-chemical examinations

Corrosion inhibition performance of two pyrazole derivatives, namely N-((1H-pyrazol-1-yl)methyl)pyrimidin-2-amine (PPA), 2-(((1H-pyrazol-1-yl)methyl)amino)benzoic acid (PMB), carbon steel (CS) was assessed in 1 M HCl medium by means of electrochemical impedance spectroscopy (EIS), weight loss, potentiodynamic polarization measurements (PDP), Uv–visible spectroscopy, and scanning electron microscopy with energy dispersive X-ray (SEM- EDX), as well as molecular modeling techniques. Results indicated that the inhibition efficiencies increased with the concentration of inhibitor, but decreased proportionally with temperature to reach a maximum of 94 % for PPA and 92 % for PMB at 10−3 M and 303 K, respectively, whereas it was 76.9 and 72.3 %, respectively, at 10−3M and 333 K. PDP plots reveal the anodic-type behavior of PPA while the mixed-type behavior of PMB. The EIS plots showed that charge transfer resistance increased and double-layer capacitance decreased with increasing the concentration of studied inhibitors due to the adsorption of inhibitor molecules on the CS surface. Moreover, the adsorption of pyrazole derivatives on the CS surface obeys the Langmuir adsorption isotherm and contains a chemisorption mechanism. Thermodynamic parameter magnitudes suggest that pyrazole derivatives were physiosorbed on the CS surface. SEM-EDX revealed the formation of an adsorption-related protective inhibitor film on the CS surface. Theoretical studies using density functional theory (DFT) for PPA and PMB molecules are performed in gas and aqueous phase conditions. The calculated data are in good agreement with the experimental results. Molecular Dynamic simulations (MDS) exhibit that the neutral and protonated forms of PPA and PMB adsorb on Fe (110) surface with a parallel mode.

Heparin-Induced Changes of Vascular Endothelial Growth Factor (VEGF165) Structure.

Vascular endothelial growth factor-A (VEGF-A), a secreted homodimeric glycoprotein, is a critical regulator of angiogenesis in normal and pathological states. The binding of heparin (HE) to VEGF165 (the major form of VEGF-A) modulates the angiogenesis-related cascade, but the mechanism of the observed changes at the structural level is still insufficiently explored. In the present study, we examined the effect of HE on the structural and physicochemical properties of recombinant human VEGF165 (rhVEGF165). The HE binding results in an increase of hydrophobic surface exposure in rhVEGF165 without changes in its secondary structure. Differential scanning calorimetry measurements for intact and HE-bound rhVEGF165 reveals the absence of any pronounced thermally induced transitions in the protein in the temperature range from 20 to 100 °C. The apolar area increase during the heparin binding explains the pronounced HE-induced oligomerization/aggregation of rhVEGF165, as studied by chemical glutaraldehyde cross-linking and dynamic light scattering. Molecular modeling and docking techniques were used to model the full structure of dimeric VEGF165 and to reveal putative molecular mechanisms underlying the function of the VEGF165/HE system. In general, the results obtained can be a basis for explaining the modulating effect of HE on the biological activity of VEGF-A.

Investigation of the behavior of alpha casein upon binding to fluvastatin and pitavastatin: A spectroscopic study and molecular modeling

The interaction between alpha casein (α-CN) and two drugs, fluvastatin (FLU) and pitavastatin (PIT) was investigated using fluorescence, UV absorption and FTIR. In addition, the binding site was established by applying molecular modeling technique. Fluorescence data suggested that FLU and PIT quench the intrinsic fluorescence of α-CN. The binding constants for the interaction of FLU and PIT with α-CN were found to be (8.18±0.08)×104 M-1 and (9.04±0.07)×104 M-1, respectively, indicating that the binding affinity of PIT to α-CN was higher than that for FLU. The number of binding site FLU and PIT per α-CN were 1.06 and 1.04 respectively. Docking calculation showed the probable binding sites of FLU and PIT are located in the hydrophobic core of α-CN where the FLU and PIT are lined by hydrophobic residues and make three and four hydrogen bonds with FLU and PIT respectively. Simulation, molecular docking and experimental data reciprocally supported each other. Therefore, it can be concluded that α-CN can act as a carrier of FLU and PIT drugs.

Computational Chemistry and Molecular Modeling Techniques for the Study of Micropeptin EI-964: Insights into Its Chemical Reactivity and Potential Pharmaceutical Properties

Computational Chemistry and Molecular Modeling Techniques for the Study of Micropeptin EI-964: Insights into Its Chemical Reactivity and Potential Pharmaceutical Properties

Revolutionizing antiretroviral therapy for human immunodeficiency virus/AIDS: A computational approach using molecular docking, virtual screening, and 3D pharmacophore building to address therapeutic failure and propose highly effective candidates.

In the context of human immunodeficiency virus (HIV) treatment, the emergence of therapeutic failures with existing antiretroviral drugs presents a significant challenge. This study aims to employ advanced molecular modeling techniques to identify potential alternatives to current antiretroviral agents. The study focuses on three essential classes of antiretroviral drugs: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Computational analyses were performed on a database of 3,343,652 chemical molecules to evaluate their binding affinities, pharmacokinetic properties, and interactions with viral reverse transcriptase and protease enzymes. Molecular docking, virtual screening, and 3D pharmacophore modeling were utilized to identify promising candidates. Molecular docking revealed compounds with high binding energies and strong interactions at the active sites of target enzymes. Virtual screening narrowed down potential candidates with favorable pharmacological profiles. 3D pharmacophore modeling identified crucial structural features for effective binding. Overall, two molecules for class 1, 7 molecules for class 2, and 2 molecules for class 3 were selected. These compounds exhibited robust binding affinities, interactions with target enzymes, and improved pharmacokinetic properties, showing promise for more effective HIV treatments in cases of therapeutic failures. The combination of molecular docking, virtual screening, and 3D pharmacophore modeling yielded lead compounds that hold potential for addressing HIV therapeutic failures. Further experimental investigations are essential to validate the efficacy and safety of these compounds, with the ultimate goal of advancing toward clinical applications in HIV management.

PyThinFilm: Automated Molecular Dynamics Simulation Protocols for the Generation of Thin Film Morphologies.

The performance of organic optoelectronic devices, such as organic light-emitting diodes (OLEDs) and organic solar cells (OSCs), is intrinsically related to the molecular-scale morphology of the thin films from which they are composed. However, the experimental characterization of morphology at the molecular level is challenging due to the often amorphous or at best semicrystalline nature of these films. Classical molecular modeling techniques, such as molecular dynamics (MD) simulation, are increasingly used to understand the relationship between morphology and the properties of thin-film devices. PyThinFilm (github.com/ATB-UQ/PyThinFilm) is an open-source Python package which allows fully automated MD simulations of thin film growth to be performed using vacuum and/or solution deposition processes. PyThinFilm utilizes the GROMACS simulation package in combination with interaction parameters from the Automated Topology Builder (atb.uq.edu.au). Here, PyThinFilm is described along with an overview of applications in which PyThinFilm has been used to study the thin films of organic semiconductor materials typically used in OLEDs and OSCs.