Number Of H-bonds Research Articles

In Silico Evaluation of Novel Quinoline Derivatives Targeting Hepatocyte Growth Factor Receptors as Anticancer Agents

Background: Numerous methods for computer-aided drug design (CAAD) have made it possible to create and synthesize new chemical entities. The utilization of in silico techniques and structure-based drug design (SBDD) facilitate the visualization of the ligand-target binding process, in addition to allowing the prediction of receptor affinities and important binding pocket locations. Objective: The current research work was carried out to recognize novel quinoline derivatives designed specifically to bind with hepatocyte growth factor (HGF) receptors. Materials and Methods: For the formation of quinolines derivatives, ChemAxon Marvin Sketch 5.11.5 was utilized. SwissADME and the admetSAR online web tools were exploited to predict the pharmacokinetic properties and the toxicity of compounds. Numerous software, including Autodock 1.5.7, MGL Tools 1.5.7, Biovia Discovery Studio Visualizer v20.1.0.19295, Procheck, Protparam tool, and PyMOL, were also used to determine the ligand-receptor interactions of derivatives of quinoline with the target receptor (PDB -1R0P). Results: Based on in silico research, it was found that all compounds were less toxic, orally bioavailable, and had the proper pharmacokinetic properties. When compared to the commonly used drug gefitinib, the docking scores of all newly created derivative compounds were higher. Conclusion: An increased binding energy, the number of H-bonds generated, and interactions with quinoline analogues are significant parameters to be considered while constructing compounds that are most appropriate for additional investigation. The favorable pharmacokinetic profile of quinoline moiety was found to enhance its potential as a novel lung cancer treatment alternative and may help medicinal chemists to carry out more thorough in vitro, in vivo, chemical, and pharmacological research studies.

Structural Bioinformatics Study Revealed Inhibition of Acute Myeloid Leukemia through Targeting Inhibition BTG2 Gene by Using Herbal Medicine

Acute myeloid leukemia (AML) is responsible for more than 40% of adult patients suffering from adverse effects leading to death around the world. The B-cell translocation gene 2 (BTG2) gene work as a tumor suppressor. In this study, a list of medicinal herb compounds and drugs was investigated for their pharmacokinetic properties and cytotoxicity by applying the SwissADME, pkCSM, and Molsoft LLC websites. The molecular docking between the medicinal herbs and AML-standard drugs against the human BTG2 gene was carried out by Auto-dock Vina. Furthermore, protein-protein interactions, gene ontology, and gene enrichment analysis were investigated to display the biological pathways related to BTG2. Also, molecular dynamics simulation was examined to study the behavior of the BTG2 protein and the protein-ligand complex. The present work exhibited that hesperidin displayed the highest binding affinity of −7.0 kcal/mol when interacting and docked against the BTG2 protein, while Cytarabinee and daunorubicin had binding affinity of 5.0 and 5.8 kcal/mol, respectively. The PPI highlighted 101 interactions with P-values less than 10 e-16., and the highest similarity score of 0.13 was found in P53 transcriptional gene network pathways. Interestingly, gene enrichment analysis illustrated that RNA degradation was the most significant enrichment pathway. Also, BTG2 contributes to the P53 signaling pathway in chronic myeloid leukemia. Via GADD45A gene. Molecular dynamics simulations were carried out for the highest binding docking (BTG2-hesperidin) complex, and the results revealed conformational alterations with more pronounced surface residue fluctuations in BTG2. The direct interaction of hesperidin with various crucial amino-acid residues like HIS 49, CYS 67, ARG 69, ASN 71, ASP 75, ARG 112, and THR 101 causes modifications in these residues, which ultimately attenuate the activity of the BTG-2 protein. The molecular dynamics determine the four numbers of H-bonds for executing the interaction between BTG2 and hesperidin. The best residue with high energy around all poses is Arg69. Finally, the present work highlighted that hesperidin was the highest phytochemical compound binding to BTG2 protein.

Investigation of Novel Quinoline Derivatives Targeting Epidermal Growth Factor Receptors as Anticancer Agents a Computational Approach

Background: Newer chemical entities are created and synthesis has been made feasible by a variety of computer-aided drug design (CAAD) techniques. In addition to facilitating the visualisation of the ligand-target binding process, the application of in silico methodologies and structure-based drug design (SBDD) allows for the prediction of receptor affinities and significant binding pocket locations. Objective: The goal of the current study was to identify new quinoline derivatives by computational methods specially designed to bind the EGFR receptor in the treatment of breast cancer. Materials and Methods: ChemAxon Marvin Sketch 5.11.5 was used to create derivatives of quinolines. The admetSAR online web tools and SwissADME were utilised to forecast the toxicity and pharmacokinetic characteristics of several substances. A multitude of software programmes, such as Autodock 1.1.2, MGL Tools 1.5.6, Procheck, Protparam ExPasy tool, PyMOL, and Biovia Discovery Studio Visualizer v20.1.0.19295 were also employed to ascertain the ligand-receptor interactions between quinoline derivatives and the target receptor (PDB -5GNK). Result: Almost all components were shown to be less hazardous, orally consumable and to have the appropriate pharmacokinetic characteristics based on in silico study. All newly generated derivative compounds have higher docking scores when compared to the widely used medication sorafenib. Conclusion: Interactions with quinoline analogues boost binding energy and the number of Hbonds produced, making them a suitable place to start when creating compounds for further exploration. The quinoline moiety increases its potential as a novel therapy alternative for breast cancer and could facilitate more comprehensive in vivo, in vitro, chemical-based, and pharma studies by medicinal chemists.

Durability of epoxy and vinyl ester polymers in wet, seawater, and seawater sea sand concrete environments: Molecular dynamics simulations

Epoxy and vinyl ester (VE) deteriorate under harsh environmental conditions typical of marine and offshore applications. Enhancing their performance requires a deeper understanding of their molecular-level interactions with these environments. This study uses molecular dynamics simulations to investigate the behavior of epoxy and VE under dry, wet, Na2SO4, NaCl, NaOH, KOH, and simulated seawater sea sand concrete (SWSSC) pore solution environments. The effect of temperatures ranging from 300 K to 368 K was also explored. Key parameters, such as radial distribution function, hydrogen bond dynamics, diffusion coefficients of water molecules and ions, swelling ratio, and glass transition temperature (Tg), were analyzed. Results show that epoxy is more sensitive to environmental effects than VE. In the dry state, three types of hydrogen bonds (H-bonds) were identified, with 64 % of the hydroxyl (OH) group involved in epoxy and 34 % in VE. As temperature increases, polymer chain interactions weaken, leading to a decrease in H-bonds, with epoxy showing a faster decline. Absorbed water molecules accumulate near the polymer polar sites, particularly at the OH groups, breaking some polymer-polymer H-bonds and forming new ones with the polymer polar sites. The hydrogen atoms of most absorbed water molecules orient away from the OH group, creating binding sites for water clustering through water-water H-bonds, leading to plasticization and potential hydrolytic degradation. Ions increase the number of polymer-water H-bonds, significantly decreasing polymer-polymer H-bonds (by 59.22 % for epoxy and 51.52 % for VE in SWSSC), thus accelerating material deterioration. Free volume distribution and dynamics, the transition between bound and free water, hydrogen bond dynamics, as well as ion hydration and dehydration collectively influence the water diffusion process in the polymer networks. Ion species diffuse much slower than water molecules, with epoxy showing higher permeability to Cl- and OH- compared to VE. Glass transition temperature (Tg) of both polymers is sensitive to environmental exposure, with epoxy being more affected. The detrimental effect on Tg is ranked as SWSSC > KOH > NaOH > NaCl > Na2SO4 > Wet. These findings provide new nanoscale insights into the interactions between polymers and SWSSC environments, offering a foundation for accurately predicting the durability of polymer-reinforced SWSSC.

Stability and conformation of DNA-hairpin in cylindrical confinement

We conducted atomistic Molecular Dynamics (MD) simulations of DNA-Hairpin molecules encapsulated within Single-Walled Carbon Nanotubes (SWCNTs) at a temperature of 300 K. Our investigation revealed that the structural integrity of the DNA-Hairpin can be maintained within SWCNTs, provided that the diameter of the SWCNT exceeds a critical threshold value. Conversely, when the SWCNT diameter falls below this critical threshold, the DNA-Hairpin undergoes denaturation, even at a temperature of 300 K. The DNA-Hairpin model we employed consisted of a 12-base pair stem and a 3-base loop, and we studied various SWCNTs with different diameters. Our analyses identified a critical SWCNT diameter of 3.39 nm at 300 K. Examination of key structural features, such as hydrogen bonds (H-bonds), van der Waals (vdW) interactions, and other inter-base interactions, demonstrated a significant reduction in the number of H-bonds, vdW energy, and electrostatic energies among the DNA hairpin's constituent bases when confined within narrower SWCNTs (with diameters of 2.84 nm and 3.25 nm). However, it was observed that the increased interaction energy between the DNA-Hairpin and the inner surface of narrower SWCNTs promoted the denaturation of the DNA-Hairpin. In-depth analysis of electrostatic mapping and hydration status further revealed that the DNA-Hairpin experienced inadequate hydration and non-uniform distribution of counter ions within SWCNTs having diameters below the critical value of 3.39 nm. Our inference is that the inappropriate hydration of counter ions, along with their non-uniform spatial distribution around the DNA hairpin, contributes to the denaturation of the molecule within SWCNTs of smaller diameters. For DNA-Hairpin molecules that remained undenatured within SWCNTs, we investigated their mechanical properties, particularly the elastic properties. Our findings demonstrated an increase in the persistence length of the DNA-Hairpin with increasing SWCNT diameter. Additionally, the stretch modulus and torsional stiffness of the DNA-Hairpin were observed to increase as a function of SWCNT diameter, indicating that confinement within SWCNTs enhances the mechanical flexibility of the DNA-Hairpin.

Enhancing toughness in cement-based composites: Unraveling the composite effect mechanisms of polymers and fibers through physic testing and molecular dynamics simulations

To reveal the toughening mechanism of polymers and fibers in composite applications, a combination of physical tests (uniaxial compression, flexural fracture, single fiber pull-out, scanning electron microscopy, and X-ray diffraction (XRD)) and molecular dynamics simulations have been carried out. Three polymers, i.e. ethylene-vinyl acetate copolymer (EVA), styrene-acrylate copolymer (SAE), and styrene-butadiene copolymer (SB), and two fibers, i.e. polypropylene fiber (PP) and polyvinyl alcohol fiber (PVA) are considered. Their composite effect mechanisms are explained in the viewpoint of three scales. At the macro-scale, the pull-out tests of single fiber show that the polymer increased the equivalent bond strength between the fiber and the mortar matrix. At micro-scale, it was observed from the SEM experiments that the fiber and polymer film inhibited the crack extension at different scales, besides the polymer could absorb on the fiber surface to improve the interfacial transition zone (ITZ) density around the fiber and increase the roughness of the fiber surface. At nano-scale, MD simulations demonstrate that three polymers facilitated the bond strength between PP fiber and C–S–H at the nano-scale, mainly because of the formation of Ca–O coordination bond and H-bonds between the polymers and C–S–H, and the presence of van der Waals forces between the polymers and PP fiber. However, SAE facilitated the bonding between the PVA fibers and the C–S–H, which originated from the coordination bonds formed between Ca ions on the surface of SAE and O atoms in PVA. In addition, the large number of H-bonds formed between SAE and PVA.

The structure of water-ammonia mixtures from classical and abinitio molecular dynamics.

The structure of aqueous ammonia solutions is investigated through classical molecular dynamics (MD) and abinitio molecular dynamics (AIMD) simulations. We have preliminarily compared three well-known classical force fields for liquid water (SPC, SPC/E, and TIP4P) in order to identify the most accurate one in reproducing AIMD results obtained at the Generalized Gradient Approximation (GGA) and meta-GGA levels of theory. Liquid ammonia has been simulated by implementing an optimized force field recently developed by Chettiyankandy et al. [Fluid Phase Equilib. 511, 112507 (2020)]. Analysis of the radial distribution functions for different ammonia concentrations reveals that the three water force fields provide comparable estimates of the mixture structure, with the SPC/E performing slightly better. Although a fairly good agreement between MD and AIMD is observed for conditions close to the equimolarity, at lower ammonia concentrations, important discrepancies arise, with classical force fields underestimating the number and strength of H-bonds between water molecules and between water and ammonia moieties. Here, we prove that these drawbacks are rooted in a poor sampling of the configurational space spanned by the hydrogen atoms lying in the H-bonds of H2O⋯H2O and, more critically, H2O⋯NH3 neighbors due to the lack of polarization and charge transfer terms. This way, non-polarizable classical force fields underestimate the proton affinity of the nitrogen atom of ammonia in aqueous solutions, which plays a key role under realistic dilute ammonia conditions. Our results witness the need for developing more suited polarizable models that are able to take into account these effects properly.

Modeling hydration of graphene oxide (GO) – Does size matter?

The biomedical applications of graphene-based materials become one of hot scientific and technological topics in the last few years. Flake graphene oxide (GO) is considered as one of the promising materials for biomedical use due to a number of specific properties, in particular in design of advanced drug delivery systems (DDS). The key factor in the formation of non-covalently bonded complexes for drug transport is the strength of non-covalent interactions of the carrier with both the drug and the environment. In the current work, we have focused on molecular modeling of solvation of zigzag-edged graphene oxide, functionalized with hydroxyl and carboxyl substituents. The hydration was determined from the magnitude of weak intermolecular interactions of GO with one or two water molecules. Our goal was to establish the dependence of the degree and type of functionalization, as well as the size of graphene flakes and the position of hydrophilic substituents on the number and strength of H-bonds. All calculations were performed using density functional theory (DFT) at the B3LYPD3BJ/6-311++G** level. The effect of water solvent was established using an explicit (discrete) model of solvent.

Temperature-Dependent Dielectric Relaxation Measurements of (Betaine + Urea + Water) Deep Eutectic Solvent in Hz-GHz Frequency Window: Microscopic Insights into Constituent Contributions and Relaxation Mechanisms.

A combined experimental and simulation study of dielectric relaxation (DR) of a deep eutectic solvent (DES) composed of betaine, urea, and water with the composition [Betaine:Urea:Water = 11.7:12:1 (weight ratio) and 9:18:5 (molar ratio)] was performed to explore and understand the interaction and dynamics of this system. Temperature-dependent (303 ≤ T/K ≤ 343) measurements were performed over 9 decades of frequency, combining three different measurement setups. Measured DR, comprising four distinct steps with relaxation times spreading over a few picoseconds to several nanoseconds, was found to agree well with simulations. The simulated total DR spectra, upon dissection into three self (intraspecies) and three cross (interspecies) interaction contributions, revealed that the betaine-betaine self-term dominated (∼65%) the relaxation, while the urea-urea and water-water interactions contributed only ∼7% and ∼1%, respectively. The cross-terms (betaine-urea, betaine-water, and urea-water) together accounted for <30% of the total DR. The slowest DR component with a time constant of ∼1-10 ns derived dominant contribution from betaine-betaine interactions, where betaine-water and urea-water interactions also contributed. The subnanosecond (0.1-0.6 ns) time scale originated from all interactions except betaine-water interaction. An extensive interaction of water with betaine and urea severely reduced the average number of water-water H-bonds (∼0.7) and heavily decreased the static dielectric constant of water in this DES (εs ∼ 2). Furthermore, simulated first rank collective single particle reorientational relaxations (C1(t)) and the structural H-bond fluctuation dynamics (CHB (t)) exhibited multiexponential kinetics with time scales that corresponded well with those found both in the simulated and measured DR.

Unlocking Dynamic Solvation Chemistry and Hydrogen Evolution Mechanism in Aqueous Zinc Batteries.

Understanding the interfacial hydrogen evolution reaction (HER) is crucial to regulate the electrochemical behavior in aqueous zinc batteries. However, the mechanism of HER related to solvation chemistry remains elusive, especially the time-dependent dynamic evolution of the hydrogen bond (H-bond) under an electric field. Herein, we combine in situ spectroscopy with molecular dynamics simulation to unravel the dynamic evolution of the interfacial solvation structure. We find two critical change processes involving Zn-electroplating/stripping, including the initial electric double layer establishment to form an H2O-rich interface (abrupt change) and the subsequent dynamic evolution of an H-bond (gradual change). Moreover, the number of H-bonds increases, and their strength weakens in comparison with the bulk electrolyte under bias potential during Zn2+ desolvation, forming a diluted interface, resulting in massive hydrogen production. On the contrary, a concentrated interface (H-bond number decreases and strength enhances) is formed and produces a small amount of hydrogen during Zn2+ solvation. The insights on the above results contribute to deciphering the H-bond evolution with competition/corrosion HER during Zn-electroplating/stripping and clarifying the essence of electrochemical window widened and HER suppression by high concentration. This work presents a new strategy for aqueous electrolyte regulation by benchmarking the abrupt change of the interfacial state under an electric field as a zinc performance-enhancement criterion.

Computational Study of Lactucine and its Derivatives to Investigate its Anti-cancerous Properties Targeting Apoptosis-inducing Protein

Background: Lactucine is related to the sesquiterpene lactone group of naturally occurring compounds and has a variety of pharmacological effects including anticancer properties found in Chicory, Wormwood, Laurus nobilis, Pyrethrum, Chamomile, etc. Lactucine has an anticancer effect which may induce apoptosis in cancerous cells and protect other cells from getting infected. Objective: In this study, Lactucine and its derivatives were screened, and performed their in silico docking study with the proteins involved in the apoptosis-inducing effect in human leukemia cancer. Methods: The three-dimensional structure of lactucine and its derivatives were retrieved in the SDF format. Active sites of protein structures were determined by Sitemap. LigPrep module was used for geometrical refining of chemical structures of lactucine and its derivatives. The protein preparation wizard of Maestro (Schrodinger) was used for protein preparation. From the receptor-complex structure, the cocrystallized ligands were removed from the active site position of the receptor chain. All ligands were docked using default Glide settings for a grid centered on the ligand and structure. Flexible docking was performed using the extra precision (XP) feature of Glide module. The best docking poses for the lactucine and their derivatives were selected based on their docking score. The ADMET properties of lactucine 15- oxalate have been predicted by admetSAR software. Results: Proteins and ligands three-dimensional structures were retrieved from PDB and Pubchem databases, respectively. All lactucine derivatives suitably docked on the apoptosis-inducing proteins with ample Glide scores Lactucin 15-oxalate interacts with proteins which are responsible for apoptosis with a maximum of six H-bonds. Other types of interactions are also involved, like Pi-cation, Pi-Pi stacking, salt bridges, and halogen bonds. Protein CDK-4 has shown the highest number of H-bond (LYS142 salt bridges), ALA16, VAL14, ASP99, LYS35, TYR17, and ASN145) with the Lactucin 15-oxalate. ADMET properties of lactucin 15-oxalate met with the criteria of being eligible to be a novel drug for the treatment of human leukemia cancer. The Dock score of both the Dasatinib drug and the lactucine-15-oxalate with the apoptosis-inducing protein stipulates that the selected ligand has equitable interaction with the target proteins. Conclusion: In this study, lactucine derivatives were docked with apoptosis-inducing proteins for the prediction of its anticancer effect. Lactucin15-oxalate has shown the highest binding affinity for the CDK-4 target and can be used as a lead compound for cancer treatment. Glide and Dock score for docking of lactucin 15-oxalate with CDK-4, well as the number of hydrogen bonding, is in agreement to use this ligand for study. These in silico results are valuable to proceed with the in vitro and in vivo studies related to the anti-cancer role of lactucin 15-oxalate.

Solar-driven abnormal evaporation of nanoconfined water.

Intrinsic water evaporation demands a high energy input, which limits the efficacy of conventional interfacial solar evaporators. Here, we propose a nanoconfinement strategy altering inherent properties of water for solar-driven water evaporation using a highly uniform composite of vertically aligned Janus carbon nanotubes (CNTs). The water evaporation from the CNT shows the unexpected diameter-dependent evaporation rate, increasing abnormally with decreasing nanochannel diameter. The evaporation rate of CNT10@AAO evaporator thermodynamically exceeds the theoretical limit (1.47 kg m-2 hour-1 under one sun). A hybrid experimental, theoretical, and molecular simulation approach provided fundamental evidence of different nanoconfined water properties. The decreased number of H-bonds and lower interaction energy barrier of water molecules within CNT and formed water clusters may be one of the reasons for the less evaporative energy activating rapid nanoconfined water vaporization.

Effect of Hydrophobic Side-Group Chemistry on Conformation, Intermolecular Structure and Dynamics of Cationic Poly(Vinyl Amine) in Aqueous Solution

Atomistic molecular dynamics simulations of the single chains of cationic polyelectrolytes of atactic poly(vinyl amines) (PVAm) modified by hydrophobic side-groups, poly(N-ethyl-n-vinyl amine) (ethyl-PVAm) and poly(N-benzyl-n-vinyl amine) (benzyl-PVAm), in aqueous solution, were carried out over the entire range of degree-of-ionization, f. These polymers, to our knowledge, were studied here by molecular simulations for the first time. The interplay of electrostatic interactions, excluded volume, hydrophobic effect, hydrogen bonding and counter-ion interaction with hydrophobic-polyions, is analyzed. The conformational transition of the polyelectrolyte chain from a coiled to an extended state was gradual and was observed for 0.3 < f < 0.7. Ethyl-PVAm and benzyl-PVAm exhibited similar values of radius-of-gyration Rg and end-to-end distance R for f > 0.5, in agreement with available experimental data. The more hydrophobic benzyl-PVAm showed a more extended conformation with a preference for trans states in the backbone. The change in chain expansion with respect to f was more for benzyl-PVAm as compared to ethyl-PVAm. The relaxation time of polymer-water H-bonds increased with f and the hydrophobicity of the polymer chain, with faster decay for ethyl-PVAm. The water molecules solvating the hydrophobic PVAm’s showed dynamical restriction due to bulky hydrophobic side-groups resulting in long-lived H-bonds. The number of polymer-water H-bonds showed a transition at a certain charge, which influenced the complex interplay of steric effect, hydrophobic effect and solvation.

A wearable strain sensor based on self-healable MXene/PVA hydrogel for bodily motion detection

Developing flexible, stretchable, and self-healing wearable electronic devices with skin-like capabilities is highly desirable for healthcare and human-machine interaction. Hydrogels as a promising sensing material with crosslinked polymer networks have received widespread attention for decades. However, sensors based on hydrogels suffer from low sensitivity and stability due to their poor electrical conductivity or the movement of nanofillers in hydrogel networks. Herein, a stable, sensitive, and self-healing strain sensor is fabricated by the Ti3C2Tx MXene nanosheets/polyvinyl alcohol (PVA) hydrogel (T-hydrogel). The introduction of MXene increases the number of H-bonds in the PVA hydrogel network and enhances the conductivity, resulting in high sensitivity, stability, and self-healing character. The self-healing T-hydrogel-based strain sensor has a performance close to that of the original sensor. In addition, the device is capable of detecting bodily motions, indicating the potential application in the field of human health monitoring and human-computer interaction.

Investigating with molecular dynamics, self-assembly of enantiomeric forms of PLA/functionalized-PLA in different solvent conditions

Poly-lactic acid is a versatile biopolymer with excellent mechanical and biological properties, making it suitable for various industrial applications. Enantiomeric forms of PLA can self-assemble into macromolecular nanoparticles with tunable functionalities, further enhancing their potential applications. In this study, the solvated behavior of single and multiple chains of enantiomeric forms of native and functionalized PLA chains in different solvents is investigated via MD simulations to understand the molecular level interactions between them. Self-assembled polymeric structures are analyzed based on the evaluation of their radius of gyration and solvent accessible surface area. Molecular interactions between PLA-PLA and PLA-solvent are explored by examining the number of inter-molecular h-bonds, radial distribution functions and PLA-solvent vdW/coulombic interactions. Outcomes provide insights into the comparative stability of PLA enantiomeric forms in different solvents, the role of solvents in self-assembly, the anticipated impact of functionalization on the self-assembly process and the favorability of stereocomplexation in different solvents.

Computational Molecular Docking and In-Silico, ADMET Prediction Studies of Quinoline Derivatives as EPHB4 Inhibitor

Background:: The creation and development of novel chemical entities is made possible by numerous computer-aided drug design techniques. The ability to visualize the ligand-target interaction and forecast the important holding pocket locations and affinities of ligands to their intended macromolecules is made possible by pharmacophore-based drug design and understanding in-silico methodologies. Objective:: The aim of the current investigation was to find novel 2-chloroquinoline-3-carboxamide derivatives that target the Ephrin B4 (EPHB4) receptor to treat cancer. Materials and Methods:: Chem Axon Marvin Sketch 5.11.5 was used to create derivatives of 2-chloroquinoline-3-carboxamide. The physicochemical characteristics of compounds as well as their toxicity were predicted using SwissADME&amp; the admet SAR online software’s. Molecular docking technology was used to examine the ligand-receptor interactions of 2-chloroquinoline-3-carboxamide derivatives with the target receptor (PDB- 6FNM) using a variety of software’s, including Autodock1.1.2,Procheck, ProtParam tool, Biovia Discovery Studio Visualizer v20.1.0.19295, MGL Tools 1.5.6, PyMOL, and were all included. Results:: All developed compounds were determined to be orally bioavailable, less toxic, and have acceptable pharmacokinetic properties according to in silico studies. In comparison to the traditional medication Erdafitnib, all new compounds displayed higher docking scores. Conclusion:: The increase in binding energy and the number of H-bonds created by novel derivatives with interactions at distances below 3.40A provide a helpful starting point for formulating and synthesizing compounds that are most suitable for additional research. The application of the 2- chloroquinoline-3-carboxamide moiety as a potential new cancer treatment candidate is supported by its pharmacokinetics &amp;toxicological profile, which may aid medicinal chemists in conducting more in-depth in vitro, in vivo chemical and pharmacological studies.

Structural and energetic analysis of NS5 protein inhibition by small molecules in Japanese encephalitis virus using machine learning and steered molecular dynamics approach

One of the viral diseases that affect millions of people around the world, particularly in developing countries, is Japanese encephalitis (JE). In this study, the conserved protein of this virus, that is, non-structural protein 5 (NS5), was used as a target protein for this study, and a compound library of 749 antiviral molecules was screened against NS5. The current study employed machine learning-based virtual screening combined with molecular docking. Here, three hits (24360, 123519051 and 213039) had lower binding energies (< −8 kcal/mol) than the control, S-Adenosyl-L-homocysteine (SAH). All the compounds showed significant H-bond interactions with functional residues, which were also observed by the control. Molecular dynamics simulation, MM/GBSA for binding free energy analysis, principal component analysis and free energy landscape were also performed to study the stability of the complex formation. All three compounds had similar root mean square deviation trends, which were comparable to the control, SAH. Post-MD, the 123519051-receptor complex had the highest number of H-bonds (4 to 5) after the control, out of which three exhibited the highest percentage occupancy (50%, 24% and 79%). Both docking and MD, 123519051 showed an H-bond with the residue Gly111, which was also found for the control-protein complex. 123519051 showed the lowest binding free energy with ΔG bind of −89 kJ/mol. Steered molecular dynamics depicted that 123519051 had the maximum magnitude of dissociation (1436.43 kJ/mol/nm), which was more than the control, validating its stable complex formation. This study concluded that 123519051 is a binder and could inhibit the protein NS5 of JE. Communicated by Ramaswamy H. Sarma

How do physicochemical properties contribute to inhibitory activity of promising peptides against Zika Virus NS3 protease?

Flavivirus diseases' cycles, especially Dengue and Yellow Fever, can be observed all over Brazilian territory, representing a great health concern. Additionally, there are no drugs available in therapy. In this scenario, in silico methodologies were applied to obtain physicochemical properties, as well as to better understand the ligand-biological target interaction mode of 20 previously reported NS2B/NS3 protease inhibitors of Dengue virus. Since catalytic site of flavivirus hold similarities, such as the same catalytic triad (His51, Asp75 e Ser135), the ability of this series of molecules to fit in Zika NS3 domains can be achieved. We performed an exploratory data analysis, using statistical methodologies, such as PCA (Principal Component Analysis) and HCA (Hierarchical Component Analysis), to assist the comprehension of how physicochemical properties impact the interaction observed by the docking studies, as well as to build a correlation between the respective ranked characteristics. Based on these previous studies, peptides were selected for the dynamics simulations, which were useful to better understand the ligand-protein interactions. Information relating to, for instance, energy, ΔG, average number of hydrogen bonds and distance from Ser135 (one of the main amino acids in the catalytic pocket) were discussed. In this sense, peptides 15 (considering ΔG value and Hbond number), 7 (ΔG and energy) and 1, 6, 7 and 15 (the proximity to Ser135 throughout the dynamics simulation) were highlighted as promising. Those interesting results could contribute to future studies regarding Zika virus drug design, since this infection represents a great concern in neglected populations. The models were constructed in the ChemDraw software. The ligand parametrization was performed in the CHEM3D 17.0, UCSF Chimera. Docking simulations were carried out in the GOLD software, after the redocking validation. We used ASP as the function score. Additionally, for dynamics simulations we applied GROMACS software, exploring, mainly, free binding energy calculations. Exploratory analysis was carried out in Minitab 17.3.1 statistical software. Prior to the exploratory analysis, data of quantum chemical properties of the peptides were collected in Microsoft Excel spreadsheet and organized to obtain Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA).

Computational insights into overcoming resistance mechanisms in targeted therapies for advanced breast cancer: focus on EGFR and HER2 co-inhibition

In the present study, the formation of a heterodimer involving both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) has been explored as a potential therapeutic mechanism to inhibit the progression of breast cancer. Virtual screening using molecular docking resulted in the three hit compounds (ZINC08382411, ZINC08382438, and ZINC08382292) with minimum binding scores and commonly binding to both receptors. Further, MD simulation analysis of these complexes illustrated the high stability of these compounds with EGFR and HER2. RMSD showed that ZINC08382411 displayed the most stable RMSD of 2 - 3 Å when bound to both receptors, suggesting to have strong compatibility with the active site of the receptor. Hydrogen bond analysis showed that ZINC08382411 forms the maximum number of H-bonds (2 to 3) in both EGFR and HER2 bound complexes, with the highest occupancy of 62% and 79%, respectively. Binding free energy calculation showed that ZINC08382411 possesses maximum affinity towards both the receptors with ΔGbind = −129.628 and −164.063 kJ/mol, respectively. This approach recognizes the significance of EGFR and HER2 in breast cancer development and aims to disrupt their collaborative signaling, which is known to promote the antagonistic behavior of cancer cells. By focusing on this EGFR/HER2 heterodimer, the study offers a promising avenue for identifying a potential candidate (ZINC08382411) that may inhibit breast cancer cell growth and potentially improve patient outcomes. The study’s findings may contribute to the ongoing efforts to advance breast cancer treatment strategies. Communicated by Ramaswamy H. Sarma

Virtual Screening, Docking, and Designing of New VEGF Inhibitors as Anti-cancer Agents.

VEGFR-2 tyrosine kinase inhibitors are receiving a lot of attention as prospective anticancer medications in the current drug discovery process. This work aims to explore the PubChem library for novel VEGFR-2 kinase inhibitors. 1H-Indazole-containing drug AXITINIB, or AG-013736 (FDA approved), is chosen as a rational molecule for drug design. This scaffold proved its efficiency in treating cancer and other diseases as well. The present study used the virtual screening of the database, protein preparation, grid creation, and molecular docking analyses. The protein was validated on different parameters like the Ramachandran plot, the ERRAT score, and the ProSA score. The Ramachandran plot revealed that 92.1% of the amino acid residues were located in the most favorable region; this was complemented by an ERRAT score (overall quality factor) of 96.24 percent and a ProSA (Z score) of -9.24 percent. The Lipinski rule of five was used as an additional filter for screening molecules. The docking results showed values of binding affinity between -14.08 and -12.34 kcal/mol. The molecule C1 showed the highest docking value of -14.08 Kcal/mol with the maximum number of strong H-bonds by -NH of pyridine to amino acid Cys104 (4.22Å), -NH of indazole to Glu108 (4.72), and Glu70 to bridge H of -NH. These interactions are similar to Axitinib docking interactions like Glu70, Cys104, and Glu102. The docking studies revealed that pi-alkyl bonds are formed with unsubstituted pyridine, whereas important H-bonds are observed with different substitutions around -NH. Based on potential findings, we designed new molecules, and molecular docking studies were performed on the same protein along with ADMET studies. The designed molecules (M1-M4) also showed comparable docking results similar to Axitinib, along with a synthetic accessibility score of less than 4.5. The docking method employed in this work opens up new possibilities for the design and synthesis of novel compounds that can act as VEGFR-2 tyrosine kinase inhibitors and treat cancer.