Free Energy Change Research Articles

Synthesis, spectral elucidation and DNA binding studies of cadmium(II) carboxylates with nitrogen donor heteroligands

A new series of novel homoleptic and heteroleptic Cd(II) complexes using cyclopropanecarboxylic acid (HL1) and cyclopentanecarboxylic acid (HL2) as main ligands and N-donor species like 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen), and 2,9-dimethyl-1,10-phenanthroline (Me2phen) as co-ligands were prepared and characterized by FT-IR, multinuclear (1H and 13C) NMR, and UV–Visible spectroscopies. Furthermore, the crystal structure of the Cd(II) complex coordinated by cyclopentanecarboxylic acid (HL2) and 1,10-phenanthroline (phen) was explored by single crystal X-ray diffraction (SC-XRD) analysis. The crystal structure was binuclear, in which the coordination geometry around each cadmium center was distorted pentagonal bipyramidal coordination geometry. Various intermolecular interactions were accountable for stabilizing the supramolecular associations, which were seen by Hirshfeld surface analysis in terms of interatomic contacts. The spectroanalytical data of the synthesized complexes confirm the absence of the –OH band in the spectra of complexes as compared to the spectra of the free ligands, which favour the formation of complexes. The nature of complex-DNA interaction and the effect of the coordination of heteroligands on the binding strength of complexes were probed through UV–Visible spectroscopy and cyclic voltammetry. The obtained data confirm that the interaction of DNA with the complexes is dual: intercalation as well as groove binding. The DNA binding constants (Kb) and Gibb’s free energy changes (ΔG) were also determined for these complexes. This study aims to project effective drugs with the least harmful effects that could be useful for mankind against dreadful diseases.

Thermodynamic investigation of biperiden hydrochloride and cyclodextrins supramolecular systems

Isothermal titration calorimetry (ITC) and theoretical calculations were used to investigate the interaction of cyclodextrins (CDs) with biperiden hydrochloride (BPR), a drug for Parkinson’s disease treatment. Among the natural CDs, βCD demonstrated the larger equilibrium constant (Keq = 9,020), demonstrating the cavity size dependency for the interaction. Carboxymethyl-β-cyclodextrin (CMβCD) demonstrated a stronger affinity and higher intermolecular complex stability. Additionally, the Keq for the CMβCD:BPR system varied from 68,100 at 298.15 K to 31,650 at 328.15 K, with a constant standard Gibbs free energy change. The theoretical calculations demonstrated the most stable structure for the CMβCD:BPR inclusion complex.

Investigation of the impacts of several diols on the phase behavior and physico-chemical quantities associated with the Triton X-100 and antidiabetic drug mixture

Drug-surfactant interaction phenomena have received popularity in the pharmaceutical industry and technological sectors from the view point of wider applications. Herein, we aimed to investigate the clouding behavior and various thermodynamic properties of Triton X-100 (TX-100) and metformin hydrochloride drug (MNH; an antidiabetic drug) mixture in the attendance of diols followed by the cloud point measurement technique. The dosage form of metformin hydrochloride drug controls the glucose level in the blood. The different types of diols, i.e., ethylene glycol (EG), 1,2-propylene glycol (1,2-PrG), 2,3-butanediol (2,3-BD), and 1,5-pentanediol (1,5-PD) were uniformly used in this inspection. The effect of diols, with the variation of their concentrations on the clouding behavior of TX-100 + MNH mixture having fixed content of TX-100 (92.7 mmol kg−1) and MNH drug (2 mmol kg−1), were examined. The most enhanced CP value was experienced in the aqueous 1,5-PD medium, whereas the lowest CP value was observed in the aqueous EG medium. The CP values were recorded for the working system under the effect of changing concentrations of diols, which were observed to follow the sequential order: CPH2O+1,5−PD>CPH2O+2,3−BD>CPH2O+1,2−PrG>CPH2O+EG. The clouding progression of the working system was realized to be nonspontaneous as concluded from the positive free energy change (ΔGco) values. The positive and negative values of enthalpy (ΔHco) and entropy (ΔSco) change were documented, respectively, at the low and high concentrations of diols. The hydrophobic interactions amongst different components are predominant at the low concentrations of diols, whereas the electrostatic interactions are leading factors at the high concentrations of diols. Enthalpy-entropy compensation parameters were computed and interpreted with proper perceptive. The outcomes of this observation may be effective and helpful in the various industrial sectors, especially in the drug carrier system in the pharmaceutical arena.

Low-temperature fabrication of high-entropy rare earth hexaboride powders

Herein, we report a low-temperature method for synthesizing high-entropy rare earth hexaboride powders by reaction among rare earth oxides, B4C, and Al powders. Al was used as a reducing and decarburization agent in this process, which further reduced the Gibbs free energy change for the reaction of RexOy with B4C to form REB6. By investigating the influence of reacting temperature and amount of Al added on preparation of LaB6, the optimum experimental conditions of this method were determined to be 1300 °C and 2 times the stoichiometric ratio of Al. Theoretical supports were proposed to verify the feasibility for formation of high-entropy borides. Then, multicomponent hexaborides La0.5Ce0.5B6, La0.33Ce0.33Nd0.33B6, and La0.25Ce0.25Nd0.25Sm0.25B6 as well as high-entropy hexaboride La0.2Ce0.2Nd0.2Sm0.2Eu0.2B6 powders were successfully prepared by doping with Ce, Nd, Sm, and Eu on LaB6. RE elements with different radius were uniformly distributed in the multicomponent boride powders without obvious segregation. More importantly, the lattice distortion and stress induced by the element substitution contribute to the reduction of the average powder particle size. Finally, the DTA-TG curves show that rare earth hexaborides have good oxidation resistances when the temperature is below about 1000 °C.

Thermodynamically Ideal Quantum State Inputs to Any Device

We investigate and ascertain the ideal inputs to any finite-time physical process. We demonstrate that the expectation values of entropy flow, heat, and work can all be determined via Hermitian observables of the initial state. These Hermitian operators encapsulate the breadth of behavior and the ideal inputs for common thermodynamic objectives. We show how to construct these Hermitian operators from measurements of thermodynamic output from a finite number of effectively arbitrary inputs. The behavior of a small number of test inputs thus determines the full range of thermodynamic behavior from all inputs. For any process, entropy flow, heat, and work can all be extremized by pure input states—eigenstates of the respective operators. In contrast, the input states that minimize entropy production or maximize the change in free energy are nonpure mixed states obtained from the operators as the solution of a convex-optimization problem. To attain these, we provide an easily implementable gradient-descent method on the manifold of density matrices, where an analytic solution yields a valid direction of descent at each iterative step. Ideal inputs within a limited domain, and their associated thermodynamic operators, are obtained with less effort. This allows analysis of ideal thermodynamic inputs within quantum subspaces of infinite-dimensional quantum systems; it also allows analysis of ideal inputs in the classical limit. Our examples illustrate the diversity of “ideal” inputs: distinct initial states minimize entropy production, extremize the change in free energy, and maximize work extraction. Published by the American Physical Society 2024

Physicochemical Characteristics of Porous Starch Obtained by Combined Physical and Enzymatic Methods-Part 2: Potential Application as a Carrier of Gallic Acid.

Wettability measurements were performed for aqueous dispersions of native and modified corn, potato, and pea starch granules deposited on glass plates by the thin layer method using test liquids of a different chemical nature (polar water and formamide or non-polar diiodomethane). High values of the determination coefficient R2 confirm that the linear regression model describes the relationship between the wetting time and the square of the penetration distance very well, indicating the linear nature of the Washburn relationship. A change in free energy (enthalpy) during the movement of the liquid in the porous layer was determined for all starches before and after modification in contact with test liquids. Wetting times for polar liquids increased significantly (from 3 to 4 fold), especially for corn starch. The lower the value of the adhesive tension, the easier the wetting process takes place, and consequently, the adsorption process is facilitated. Adhesive tension for polar substances applies to the adsorption of hydrophilic substances, while in the case of apolar substances, adhesive tension applies to the adsorption of hydrophobic substances. For the adsorption of gallic acid on starch, the relationships obtained for polar substances are crucial. The adsorption of gallic acid by forming hydrogen bonds or, more generally, donor-acceptor (acid-base) bonds is definitely higher for corn starch than other starches. Therefore, this starch has the most significant potential for use as a carrier of gallic acid or, more broadly, compounds from the polyphenol group.

Ketalization mechanism of glycerol to biobased glycerol levulinate ketal over HZSM-5: A combined experimental and theoretical study

Methyl levulinate ketal (MLK) is a novel biobased chemical derived from glycerol via ketalization, and exploring its synthesis mechanism is of great significance for the high-value utilization of biomass resources. In this study, the ketalization reaction of glycerol was evaluated using the MLK yield calculated by the GC internal standard method. The acidity of HZSM-5 was determined by NH3-TPD. The catalyst screening experiments demonstrated that HZSM-5 in zeolites and AlCl3 in metal salts exhibited high catalytic activity in the synthesis of MLK. Furthermore, the kinetic results indicated that the HZSM-5 zeolite catalyst exhibited a lower apparent activation energy in catalyzing the synthesis of MLK compared to the metal salt catalyst AlCl3. The ketalization reactions of levulinate and glycerol catalyzed by different types of acidic sites in HZSM-5 were then investigated using the density functional theory method. A comprehensive catalytic path, free energy changes, intermediates, and transition state structures were proposed. Furthermore, the free energy barriers of ethyl levulinate ketal and butyl levulinate ketal catalyzed by HZSM-5 were calculated, and the difference between the steric hindrance effect and the electronic effect of alkyl in levulinate was compared. This study enhances the understanding of ketalization reactions and will be useful in future catalyst design studies.

Synthesis and characterisation of dipyrromethene Cu(II) complexes: A preliminary DNA intercalation study

Copper complexes of the bilirubin bile pigment have been shown to affect DNA. It was suggested that the copper ions within these metal-bilirubin therapeutics bind to bilirubin through the two dipyrromethene moieties, thus highlighting the potential therapeutic impact of these dipyrromethene moieties. Here, we report the synthesis and characterization of two bilirubin biomimetic copper complexes, CuL1 and CuL2, featuring tetrahedral dipyrromethene moieties. DNA binding studies reveal significant affinities for both complexes, with CuL1 displaying a log Ka of 4.70 ± 0.02, with a corresponding Gibbs free energy change (ΔG) of –26.8 kJ/mol at 25 °C, indicating a moderate-to-high DNA affinity. CuL2 showed a slightly higher affinity with log Ka of 4.88 ± 0.02, with a corresponding ΔG of –27.4 kJ/mol at 25 °C. These experimental findings aligned closely with computational docking G-scores, which yielded –32.9 kJ/mol for CuL1 and –34.8 kJ/mol for CuL2, respectively. Viscosity, gel electrophoresis, and absorption studies support an intercalative binding mechanism, which was further confirmed by computational docking and molecular dynamics simulations. These findings suggest that copper dipyrromethene complexes may exert therapeutic effects through DNA interaction, warranting further investigation involving in vitro cell cultures for drug development potential.

Atomic-scale insights into the electrochemical mechanisms of aluminum-sulfur batteries: A first-principles study of Al-S clusters on graphene

Aluminum-sulfur (Al-S) batteries, known for their high energy density, cost-effectiveness, and sustainability, face challenges due to limited understanding of their atomic-level electrochemical mechanisms. This study uses first-principles calculations to explore the geometric and electronic structures of Al-S clusters and their interaction with graphene substrates. Key findings include charge transfer from graphene to Al-S clusters, especially in C@Al2S6 and C@Al2S3, and moderate adsorption strength crucial for reversible cycling. Thermodynamic analysis identifies the free energy change in the transition from C@Al2S6 to C@Al2S3, while AIMD simulations confirm structural stability, providing insights for optimizing Al-S battery performance.

Making the Thermodynamic Cost of Active Inference Explicit.

When describing Active Inference Agents (AIAs), the term "energy" can have two distinct meanings. One is the energy that is utilized by the AIA (e.g., electrical energy or chemical energy). The second meaning is so-called Variational Free Energy (VFE), a statistical quantity which provides an upper bound on surprisal. In this paper, we develop an account of the former quantity-the Thermodynamic Free Energy (TFE)-and its relationship with the latter. We highlight the necessary tradeoffs between these two in a generic, quantum information-theoretic formulation, and the macroscopic consequences of those tradeoffs for the ways that organisms approach their environments. By making this tradeoff explicit, we provide a theoretical basis for the different metabolic strategies that organisms from plants to predators use to survive.

Pyranine Interaction with Amines in Micelles.

The fluorescence behavior of pyranine in anionic micellar system of sodium dodecyl sulphate was studied in the presence of selected amines. The amines included cyclopropylamine (CPA), ethylenediamine (EDA), benzylamine (BA), dibutylamine (DBA), cyclohexylamine (CHA), and polyethylenediamine (PEDA). All the studied amines quenched the intensity of pyranine. Study was performed in 0.05M and 0.1M SDS. The thermodynamic parameters were determined in order to understand the quenching of pyranine by the studied amines. Change in Gibbs free energy and quenching was found higher in 0.05M SDS concentration and was found lower when SDS concentration was increased to 0.1M SDS. Pyranine quenching by the amines studied were treated with an extended Stern-Volmer equation that produced the Stern-Volmer constant ([Formula: see text]). Binding constant (Kb), number of binding stoichiometry (n) and Gibbs free energy change (ΔGbinding) were found higher for lower surfactant concentration as compare to higher surfactant concentration. More negative (-ve) the Gibbs free energies more will be the quenching, higher will be the sensitivity and vice versa. The Gibbs free energies for all the studied amines were found in the order as cyclopropylamine > ethylenediamine > benzylamine > dibutylamine > cyclohexylamine > polyethylenediamine. Fluorescence quenching of pyranine by amines in aqueous SDS is reproducible and is useful for the determination of amines in environmental samples.

Machine Learning Approach to Vertical Energy Gap in Redox Processes.

A straightforward approach to calculating the free energy change (ΔG) and reorganization energy of a redox process is linear response approximation (LRA). However, accurate prediction of redox properties is still challenging due to difficulties in conformational sampling and vertical energy-gap sampling. Expensive hybrid quantum mechanical/molecular mechanical (QM/MM) calculations are typically employed in sampling energy gaps using conformations from simulations. To alleviate the computational cost associated with the expensive QM method in the QM/MM calculation, we propose machine learning (ML) methods to predict the vertical energy gaps (VEGs). We tested several ML models to predict the VEGs and observed that simple models like linear regression show excellent performance (mean absolute error ∼0.1 eV) in predicting VEGs in all test systems, even when using features extracted from cheaper semiempirical methods. Our best ML model (extra trees regressor) shows a mean absolute error of around 0.1 eV while using features from the cheapest QM method. We anticipate our approach can be generalized to larger macromolecular systems with more complex redox centers.

Thermodynamic characteristics and surface free energy analysis of bifonazole and lecithin with sodium dodecyl sulfate in hydroethanolic solvent systems

The thermodynamic investigations of the well-recognised antifungal drug bifonazole and lecithin with anionic surfactant sodium dodecyl sulphate have been established. The experiments were conducted using five distinct hydro-ethanolic concentrations, namely 0% v/v, 10% v/v, 30% v/v, 70% v/v, and 90% v/v ethanol, throughout a range of five temperatures (ranging 20 ℃, 25 ℃, 30 ℃, 35 ℃ and 40 ℃) with an increment of drug concentration. The study involved the determination of several parameters, including surface tension (σ), density (ρ), conductivity (κ), contact angle (θ) and surface free energy. Conductivity and surface tension data was used for calculating critical micelle concentration (CMC). CMC was utilised to calculate various thermodynamic properties, such as the standard entropy change (ΔS°m), standard Gibbs energy change (ΔG°m) and standard enthalpy change (ΔH°m) of micellization. This study represents a comparative analysis of the critical micelle concentration (CMC) by utilising surface tension and conductivity measurements. Contact angle is used to determine the hydrophobicity and hydrophilicity of the system. These investigations are valuable for examining the magnitude of hydrophobic interactions within the system, which might be used to ascertain an optimal concentration of bifonazole, lecithin and surfactant to prepare ethosomal formulations.

A Computational Approach of Anti-diabetic Potential Evaluation of Flower and Seed of Nyctanthes arbor tristis Linn

Exploring the medicinal significance of bioactive compounds through computational methods is an increasingly practiced approach in contemporary medicinal research. This study aims to assess the antidiabetic potential of compounds extracted from the plant Nyctanthes arbor tristis by evaluating their ability to inhibit the carbohydrate metabolic enzyme α-glucosidase. The research work was conducted through molecular docking calculation, molecular dynamics simulation (MDS), and ADMET prediction techniques. Among the compounds, arbortistoside-C (NAS03), and arbortristoside-D (NAS04) found in the seed of the plant were identified as hit inhibitors of the target protein with docking scores, -9.9 and -9.4 kcal/mol, respectively. The compounds showed a comparable docking score with the drug of diabetes acarbose (-8.6 kcal/mol). Geometrical parameters like radius of gyration, solvent accessibility surface, root mean square deviation, and root mean square fluctuation from MDS supported the stability of the protein-ligand complex. MMPBSA calculations demonstrated the stability and feasibility of the complex with binding free energy changes of -29.06±6.06 and -23.58±8.80 kcal/mol for compounds NAS03 and NAS04, respectively. The ADMET prediction suggested the drug-likeness of the compounds compared with that of the standard drugs. The results could be used in proposing the antidiabetic potential of the two compounds from the plant as a potential inhibitors of α-glucosidase enzyme. Further, in vitro and in vivo experiments on such compounds could be a more reliable path to validate the output of this computational research.

Black Hole Thermodynamic Free Energy as A-discriminants

Black Hole Thermodynamic Free Energy as A-discriminants

Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia.

To accurately verify the pathogenicity of variants of uncertain significance (VUS) in MUT and MMACHC genes through mass spectrometry and silico analysis. This multicenter retrospective study included 35 participating units (ClinicalTrials.gov ID: NCT06183138). A total of 3,071 newborns (within 7 days of birth) were sorted into carrying pathogenic/likely pathogenic (P/LP) variants and carrying VUS, non-variant groups. Differences in metabolites among the groups were calculated using statistical analyses. Changes in conservatism, free energy, and interaction force of MMUT and MMACHC variants were analyzed using silico analysis. The percentage of those carrying VUS cases was 68.15% (659/967). In the MMUT gene variant, we found that C3, C3/C2, and C3/C0 levels in those carrying the P/LP variant group were higher than those in the non-variant group (p < 0.000). The conservative scores of those carrying the P/LP variant group were >7. C3, C3/C0, and C3/C2 values of newborns carrying VUS (c.1159A>C and c.1286A>G) were significantly higher than those of the non-variant group and the remaining VUS newborns (p < 0.005). The conservative scores of c.1159A>C and c.1286A>G calculated by ConSurf analysis were 9 and 7, respectively. Unfortunately, three MMA patients with c.1159A>C died during the neonatal period; their C3, C3/C0, C3/C2, and MMA levels were significantly higher than those of the controls. Common variants of methylmalonic acidemia in the study population were categorized as VUS. In the neonatal period, the metabolic biomarkers of those carrying the P/LP variant group of the MUT gene were significantly higher than those in the non-variant group. If the metabolic biomarkers of those carrying VUS are also significantly increased, combined with silico analysis the VUS may be elevated to a likely pathogenic variant. The results also suggest that mass spectrometry and silico analysis may be feasible screening methods for verifying the pathogenicity of VUS in other inherited metabolic diseases.

Fabrication of Nanocellulose/Chitosan Nanocomposite Based on Loofah Sponge for Efficient Removal of Methylene Blue: Thermodynamic and Kinetic Investigations

AbstractWe established three nano-solid adsorbents: nanocellulose based on plant loofah sponge (NC), chitosan (CS), and nanocellulose/chitosan composite (CSC). These substances were employed as solid adsorbents to eliminate methylene blue (MB) dye from wastewater. Various characterization techniques were employed to investigate all the synthesized solid adsorbents, including TGA (thermogravimetric analysis), XRD (X-ray diffraction spectra), (BET) nitrogen gas adsorption-desorption, SEM (scanning electron microscope), TEM (transmission electron microscopy), FTIR (Fourier transform infrared) spectrometer, and zeta potential. According to our results, CSC showed greater thermal stability than LS and NC but lower than CS, mesoporous (2.012 nm), higher total pore volume (0.366 cm3. g− 1), specific surface area (639.3 m2. g− 1), and pHpzc of 7.22. The static adsorption of MB was well described by the Langmuir (R2 &gt; 0.9872), Temkin (R2 &gt; 0.9668), and Dubinin-Radushkevich (R2 &gt; 0.9485) models. The composite of nanocellulose and chitosan exhibited the highest Langmuir adsorption capacity (301.20 mg. g− 1) at 47 °C after a 24 h shaking period at a dosage of 2 g. L− 1 as the adsorbent and pH of 7. The adsorption of MB by the fabricated solid materials fitted well with the linear PSO (R2 &gt; 0.9806) and Elovich (R2 &gt; 0.9574) kinetic model. The enthalpy, entropy, and free energy change for the adsorption of MB onto CSC were determined to be 47.11 kJ. mol− 1, 0.172 kJ. mol− 1. K− 1, and − 3.29 kJ. mol− 1, respectively at 20 °C. Thermodynamic investigation showed that MB adsorption is spontaneous, endothermic, favorable (0 &lt; RL&lt;1, 0.017–0.313), and physisorption (EDR &lt; 8 kJ. mol− 1). Compared to the other eluents, nitric acid produced the highest desorption percentage (98.5%).

First-Principles Investigation on the Tunable Electronic Structures and Photocatalytic Properties of AlN/Sc2CF2 and GaN/Sc2CF2 Heterostructures.

Heterostructure catalysts are highly anticipated in the field of photocatalytic water splitting. AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures are proposed in this work, and the electronic structures were revealed with the first-principles method to explore their photocatalytic properties for water splitting. The results found that the thermodynamically stable AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures are indirect semiconductors with reduced band gaps of 1.75 eV and 1.84 eV, respectively. These two heterostructures have been confirmed to have type-Ⅰ band alignments, with both VBM and CBM contributed to by the Sc2CF2 layer. AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures exhibit the potential for photocatalytic water splitting as their VBM and CBM stride over the redox potential of water. Gibbs free energy changes in HER occurring on AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures are as low as -0.31 eV and -0.59 eV, respectively. The Gibbs free energy change in HER on the AlN (GaN) layer is much lower than that on the Sc2CF2 surface, owing to the stronger adsorption of H on AlN (GaN). The AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures possess significant improvements in absorption range and intensity compared to monolayered AlN, GaN, and Sc2CF2. In addition, the band gaps, edge positions, and absorption properties of AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures can be effectively tuned with strains. All the results indicate that AlN/Sc2CF2 and GaN/Sc2CF2 heterostructures are suitable catalysts for photocatalytic water splitting.

The denitrification characteristics of Na2S2O8 solution in a falling film reactor

ABSTRACT Wet scrubbing technology is an effective emission control technology for marine diesel engines. Nitric oxide (NO) is one of the main component of ship emissions, the sodium persulfate (Na2S2O8) can facilitate the NO mass transfer process to a rapid reaction. Falling film reactors are widely used in rapid gas–liquid reactions, however, the reaction characteristics of denitrification using Na2S2O8 solution in a falling film reactor are not clear, which were investigated in this paper. The factors of NO mass transfer flux were tested with the liquid–gas ratio of 15 L/m3. The effects of solution properties and temperatures on the reaction driving force were studied by calculating the chemical reaction equilibrium constants and Gibbs free energy changes. The results showed that the NO mass transfer flux increased with the increase of temperature, Na2S2O8 concentration, O2 concentration and NO concentration. NO mass transfer flux increased by 41.00% and then decreased by 2.12% as the pH value increased from 7 to 10 and then rising to 12. The Gibbs free energy changes of alkaline solutions were 114.22%−130.99% lower than those of acidic solution at 303–343 K, and the chemical reaction equilibrium constants were higher. Na2S2O8/seawater system has great application potential in marine exhaust gas purification.

Probing Dual Covalent Irreversible Inhibition of EGFR/FGFR4 by Electrophilic-Based Natural Compounds to Overcome Resistance and Enhance Combination Therapeutic Potentials and Management of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the world and accounts for the majority of cases of primary liver cancer. A crucial part of the carcinogenesis of HCC involves aberrant stimulation of the FGF19-FGFR4 signaling pathway. Therefore, FGFR4 inhibition has become a strategic therapeutic approach for the treatment of HCC. However, the clinical treatment procedure is significantly hampered by the prevalence of kinase inhibitors resistance. It was recently established that the activation of EGFR signaling was found to be one of the primary mechanisms mediating the acquired resistance to FGFR4 inhibitors, moreover, sensitivity to FGFR4 inhibitors was effectively restored by inhibiting EGFR. These results provide compelling evidence that dual inhibition of EGFR and FGFR4 could represent a viable therapeutic approach to overcome resistance, hence enhanced management of HCC. To this end, we proposed a dual irreversible inhibition strategy through covalent binding by naturally occurring electrophilic warhead-bearing compounds (curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A and andrographolide) to covalently target both EGFR and FGFR4 through cysteine residues, Cys797 and Cys552, respectively. Covalent docking and covalent molecular dynamics (MM/MDcov) simulations combined with thermodynamic binding free energy calculations were performed, and the results were compared against known potent and selective covalent EGFR and FGFR4 inhibitors with available X-ray crystal structures, Afatinib and BLU9931, respectively. Curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A, and andrographolide showed relative binding free energies of -22.85, -17.14, -12.98, -21.81, and - 19.00kcal/mol against EGFR and - 41.06, -29.45, -24.76, -40.11, and - 37.55kcal/mol against FGFR4, respectively. The mechanisms of binding were emphasized by hydrogen bonding and binding forces analysis as well as active site physicochemical profiling. The findings of this study identified that curcumin, syringolin A and andrographolide-but not eupalmerin acetate or deoxyelephantopin -could be viable dual EGFR and FGFR4 covalent irreversible inhibitors and could be implemented in HCC combination therapy protocols alone or in conjunction with other chemotherapeutic agents. Investigations of this study conclusively indicate dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for enhanced management of HCC.