Semiempirical AM1 Research Articles

Determination of in vitro antifungal activity of dihydroisoxazole dimethanol compound against dermatophytes obtained from clinical isolates and design of some new dihydroisoxazole dimethanol compounds

In this study, the in vitro antifungal activity of (3-(4-chlorophenyl)-4,5-dihydroisoxazole-4,5-diyl) dimethanol compound (1) was investigated against two pathogenic fungi species (Trichophyton mentagrophytes and Microsporum canis) and important results were obtained. The difficulty of treating fungal diseases induced us to assess the antifungal properties of dihydroisoxazole dimethanol compound. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC). The compound (1) showed an antifungal effect with MIC=12.5 µg ml-1 on M. canis and MIC=50 µg ml-1 on T. mentagrophytes, respectively. To prepare potentially more effective antifungal agents, new dihydroisoxazole derivatives (2-32) were theoretically designed. The geometrical optimization of all compounds (1-32) was performed using the semi-empirical AM-1 level. Some structural parameters of the optimized compounds (1-32) were also calculated.

Transferable Machine Learning Interatomic Potential for Bond Dissociation Energy Prediction of Drug-like Molecules.

We present a transferable MACE interatomic potential that is applicable to open- and closed-shell drug-like molecules containing hydrogen, carbon, and oxygen atoms. Including an accurate description of radical species extends the scope of possible applications to bond dissociation energy (BDE) prediction, for example, in the context of cytochrome P450 (CYP) metabolism. The transferability of the MACE potential was validated on the COMP6 data set, containing only closed-shell molecules, where it reaches better accuracy than the readily available general ANI-2x potential. MACE achieves similar accuracy on two CYP metabolism-specific data sets, which include open- and closed-shell structures. This model enables us to calculate the aliphatic C-H BDE, which allows us to compare reaction energies of hydrogen abstraction, which is the rate-limiting step of the aliphatic hydroxylation reaction catalyzed by CYPs. On the "CYP 3A4" data set, MACE achieves a BDE RMSE of 1.37 kcal/mol and better prediction of BDE ranks than alternatives: the semiempirical AM1 and GFN2-xTB methods and the ALFABET model that directly predicts bond dissociation enthalpies. Finally, we highlight the smoothness of the MACE potential over paths of sp3C-H bond elongation and show that a minimal extension is enough for the MACE model to start finding reasonable minimum energy paths of methoxy radical-mediated hydrogen abstraction. Altogether, this work lays the ground for further extensions of scope in terms of chemical elements, (CYP-mediated) reaction classes and modeling the full reaction paths, not only BDEs.

QSAR ANALYSIS USING SEMI-EMPIRICAL AM1 METHOD, MOLECULAR DOCKING, AND ADMET STUDIES OF CHALCONE DERIVATIVES AS ANTIMALARIAL COMPOUNDS

Malaria is a serious caused by protozoan parasites such as Plasmodium groups and has fatal consequences for human health. The increase in the resistance of the Plasmodium parasites toward existing antimalarial drugs prompts the exploration of novel compounds. In this study, quantitative structure-activity relationship (QSAR) analysis using the semi-empirical AM1 method was conducted to identify the optimal model that relates physicochemical properties and biological activity of chalcone derivatives. In addition, ADMET prediction and molecular docking were also carried out. Multilinear regression calculations for statistical parameters of QSAR models revealed that Model 4, with 11 independent variables, provided the best predictions and exhibited a robust correlation with antimalarial activity represented by inhibitory concentration (IC50). ADMET predictions indicated favorable absorption, distribution, metabolism, excretion, and toxicity properties, particularly for B2D, showing promising antimalarial attributes. Molecular docking studies targeting 5 mutated PfDHODH proteins revealed B2D’s potential to reach therapeutic targets efficiently. It has low docking scores for mutations I (-10.5 kcal/mol), II (-8.6 kcal/mol), and V (-10.5 kcal/mol) with RMSD < 2Å, in carrying out its role for antimalarial activity. This research successfully identifies B2D as an efficient inhibitor of PfDHODH receptors. Thus, it is a highly promising novel antimalarial drug.

Shedding light into the biological activity of aminopterin, via molecular structural, docking, and molecular dynamics analyses

In this study, the structural and anticancer properties of aminopterin, as well as its antiviral characteristics, were elucidated. The preferred conformations of the title molecule were investigated with semiempirical AM1 method, and the obtained the lowest energy conformer was then optimized by using density functional (DFT/B3LYP) method with 6-311++G(d,p) as basis set. The vibrational frequencies of the optimized structure were calculated by the same level of theory and were compared with the experimental values. The vibrational assignments were performed based on the computed potential energy distribution (PED) of the vibrational modes. The molecular electrostatic potential (MEP) and frontier molecular orbitals (HOMO, LUMO) analyses were carried out for the optimized structure and the chemical reactivity has been scrutinized. To enlighten the biological activity of aminopterin as anticancer and anti-COVID-19 agents, aminopterin was docked into DNA, αIIBβ3 and α5β1integrins, human dihydrofolate reductase, main protease (Mpro) of SARS-CoV-2 and SARS-CoV-2/ACE2 complex receptor. The binding mechanisms of aminopterin with the receptors were clarified. The molecular docking results revealed the strong interaction of the aminopterin with DNA (−8.2 kcal/mol), αIIBβ3 and α5β1 integrins (−9.0 and −10.8 kcal/mol, respectively), human dihydrofolate reductase (−9.7 kcal/mol), Mpro of SARS-CoV-2 (−6.7 kcal/mol), and SARS-CoV-2/ACE2 complex receptor (−8.1 kcal/mol). Moreover, after molecular docking calculations, top-scoring ligand-receptor complexes of the aminopterin with SARS-CoV-2 enzymes (6M03 and 6M0J) were subjected to 50 ns all-atom MD simulations to investigate the ligand-receptor interactions in more detail, and to determine the binding free energies accurately. The predicted results indicate that the aminopterin may significantly inhibit SARS-CoV-2 infection. Thus, in this study, as both anticancer and anti-COVID-19 agents, the versatility of the biological activity of aminopterin was shown. Communicated by Ramaswamy H. Sarma

Quantitative Relationships Between Structure and Activity of Gamma-Carboline Derivative Compounds as Anti-Bovine Viral Diarrhea Virus (BVDV) Using Semi-Empirical AM1 Method

This research aims to study the quantitative structure and activity relationship (QSAR) of gamma-carboline derivative compounds as anti-BVDV agents to get an equation that can predict the value of the anti-BVDV activity of gamma-carboline derived compounds. The research material is experimental EC50 data that convert to anti-BVDB activity. 14 gamma-carboline derivative compounds are divided into 2 groups, namely, 11 fitting compounds and 3 test compounds. QSAR analysis is based on multilinear regression calculations of the fitting compound by plotting the EC50 log as the dependent variable and the descriptor as the independent variable. The used descriptors are atomic net charge (q) and dipole moment (µ), which are involved in calculations using the AM1 semiempirical quantum mechanics method. In addition, the partition coefficient of n-octanol/water (Log P), molecular polarizability (α), molecular weight (BM), Van Der Waals surface area (A vdw), Van Der Waals volume (V vdw), and index of refraction (RD) are obtained from QSAR properties. The resulting QSAR equation is: Log pEC50 = -48.670 – 124.801 (qC11) – 12.661 (α) – 0.918 (µ) – 0.876 (RD) – 0.999 (Log P) + 1.863 (BM) + 0.043 (V vdw) with n = 14; r = 0.937; r2 = 0.878; SD = 0.244; Fcount/Ftable = 1.466; PRESS = 0.749; Sig. = 0.02 This equation can be used as an initial guide for designing the structure of new compounds of the gamma-carboline class by considering some of the most influential descriptors. Consequentially, new compounds can be designed that have a smaller predicted EC50 value than the known compounds derived from gamma-carboline.

Reliable gas-phase tautomer equilibria of drug-like molecule scaffolds and the issue of continuum solvation.

Accurate calculation of relative tautomer energies in different environments is a prerequisite to many parameters of relevance in drug discovery. This work provides a thorough benchmark of the semiempirical methods AM1, PM3 and GFN2-xTB, the force-field OPLS4, Hartree-Fock and HF-3c, the density functionals PBEh-3c, B97-3c, r2SCAN-3c, PBE, PBE0, TPSS, r2SCAN, ω-B97X-V, M06-2X, B3LYP, B2PLYP, and second-order perturbation theory MP2 versus the gold-standard coupled-cluster DLPNO-CCSD(T) using the def2-QZVPP basis set. The outperforming method identified is M06-2X, whereas r2SCAN-3c is the best-perfoming one in the set of cost-optimized methods. Application of the two methods on a challenging subset from the SAMPL2 challenge provides evidence that deviations from experiment are caused by deficiencies of current continuum solvation methods.

Association of 5,5′-Dibromo-o-Cresolsulfonphthalein Anions with Dye Cations in Aqueous Solution

The formation of associates in aqueous solutions between single- or double-charged anions of 5,5′-dibromo-o-cresolsulfonphthaleine and single-charged cations of cyanine dyes (quinaldine blue, quinaldine red) has been considered. Based on the spectrophotometric data, the equilibrium constants of the association were analyzed. The energy of cation-anion interactions (standard enthalpy of formation of ions and associates) was determined by the semi-empirical AM1 method and probable structures of associates were set. The consistency between experimental spectrophotometric and calculated quantum chemical data is discussed.

Comparison of quantum mechanics protocols during the evaluation of quantitative structure-retention relationships supported by genetic-algorithm multiple linear regression

While developing Quantitative Structure-Retention Relationships (QSRR) models it is crucial to construct a data matrix, consisting of both experimentally designated values (the ones that are being modelled) and molecular descriptors, representing physicochemical properties in form of numbers. In order to designate those descriptors, studied compounds need to be modelled and optimized using molecular modelling methods. From a variety of possible choices, semi-empirical AM1 (being an often discredited method due to the fact that it is quick and provides various approximations) and DFT (being a complex, quantum mechanics-based method, which is more time-consuming yet still bases on approximations) are one of the most popular. In this study one took a set of carefully chosen compounds used to model retention on C18 column, and modelled their molecules using both of those techniques, which were afterwards subjected to Genetic-Algorithm Multiple Linear Regression (GA-MLR) in order to derive and compare achieved models and their parameters. Study found that for the tested chromatographic system (C18 column and a set of model fifteen compounds) there is no advantage in using DFT over AM1, despite common modelling principles. What is more important, the developed models are accurate and use very simple descriptors, which can be easily calculated without any need for complex 3D modelling of structures. The derived models enabled also to assess the physicochemical properties of the tested column finding slight similarities and dissimilarities between the applied models.

Study of Stability and Reactivity of Cyclopolic Acid Compounds and Their Derivatives Using Semi-empirical Methods AM1 and PM3

The semi-empirical method is a method can be selected in computational chemistry. This method can be used to study the stability and reactivity of cyclopolic acid compounds and their derivatives. This method is simple method in optimizing a compound in calculating the parameters possessed by the atom. Cyclopolic acid is an organic compound that can be found in corn and beans. Analysis using two methods on HyperChem Professional application are AM1 and PM3. Analysis Result has shown the that total energy and gradient of each compound do not have significant differences in calculations. As in the structure of 2-formyl-3-(hydroxymethyl)-6-methoxy-5-methylterephthalic acid has a total energy of -80608.1868567 (kcal/mol) and a gradient of 0.0898817 (kcal/mol/Ang) with the AM1 method and total energy of -74935.9180118 (kcal/mol) and a gradient of 0.0874369 (kcal/mol/Ang) with the PM3 method. The stable structure is in the structure of the 2-formyl-3-(hydroxymethyl)-6-methoxy-5-methylterephthalic acid based on the calculation of the total energy and gradient. Meanwhile, according to the calculation of the difference between LUMO-HOMO, it has different results. Where according to the calculation of the energy difference between LUMO-HOMO, the most stable compound structure is the structure of 2-formyl-3-(hydroxymethyl)-4-isocyano-6-metoxy-5-methylbenzoic acid but is not reactive. Likewise, the 2-formyl-4-hidroxy-3-(hydroxymethyl)-6-methoxy-5-methylbenzoic acid, 2-formyl-3-(hydroxymethyl)-6-methoxy-5-methyl-4-(oxo-λ6-methyl)benzoic acid and 2-formyl-3-(hydroxymethyl)-6-methoxy-5-methylterephthalic acid are reactive but unstable compound structure.

Spectroscopic Determination of Dissociation Constants of Some 4- nitrobenzaldehyde-4-substituted phenyl-1-carbonylhydrazones in Sodium Hydroxide Media

Purpose: Hydrazones are a class of azomethines with a wide spectrum of pharmacological properties which are influenced by pH of the media. The purpose of this study was investigation of acid-base properties of five 4-nitrobenzaldehyde-4-substitutedphenyl1-carbonylhydrazones in sodium hydroxide media (14>pH>7). Method: The dissociation process was followed by UV-Vis spectroscopy, in the ethanol-water (V/V, 1:1) solutions, at room temperature. Semiempirical methods AM1 and PM3 were applied for determination of the deprotonation enthalpies. Results: The changes in the UV-Vis spectra, as well as the deprotonation enthalpies, suggested that the dissociation process for four investigated hydrazones with an amide group took place in one step. The exception with two dissociation steps was hydrazone with amide and hydroxyl group. The pH region of dissociation was from pH 10.8 to pH 11.6 for the first step and between pH 11.7 and pH 12.1 for the second step of dissociation. The influence of the ethanol on the UV-Vis spectra was eliminated by the method of Characteristic Vector Analyses (CVA). The stoichiometric dissociation constants were determined numerically (pKHA = n·pH + logI) and graphically (intercept of the dependence of logI on pH) from the absorbance data using experimental and reconstructed UV-Vis spectra, at three different ionic strengths. Thermodynamic dissociation constants were estimated graphically as an intercept of dependence of dissociation constant on the square root of the ionic strength. Conclusion: The obtained results demonstrated that the influence of the substituents on pKHA values was not significant, except for hydrazone with amide and hydroxyl group. Namely, the dissociation of the amide group of this hydrazone was retarded due to the influence of the phenolic group.

Biological activity, molecular docking, and ADME predictions of amphibine analogues of Ziziphus spina-christi towards SARS-CoV-2 Mpro

The main protease of the SARS-CoV-2 virus, SARS-CoV-2 Mpro, can be discovered as a promising target to treat the COVID-19 pandemic. The peptide-based inhibitors may present better options than small molecules for inhibits SARS-CoV-2 Mpro. Ziziphus spina-christi species reported have a peptide-based of alkaloids group, i.e. Amphibine that the analogues can be identified the potential as an inhibitor of SARS-CoV-2 Mpro. The compound structure was drawn and optimized using semi-empirical AM-1 method using Quantum ESPRESSO v.6.6, then the biological activity using PASS Prediction server and molecular docking simulation using MGLTools 1.5.6 with AutoDock 4.2 were performed. Afterward, the ADME profiles were predicted using the SWISS-ADME server. PASS server was predicting Amphibine B-F and H showed potency both as antiviral and as a protease inhibitor. The molecular docking simulation of Amphibine analogues showed lower binding energy than the native ligand. The binding energy of the native ligand was −7.69 Kcal/mol compared to the lowest binding energy of Amphibine analogues was −10.10 Kcal/mol (Amphibine-F). The ADME prediction showed, as an oral drug Amphibine-F has the best bioavailability, Amphibine-B, C, and D have good bioavailability, and Amphibine-E and H have poor bioavailability. Concluded, Amphibine B-F and H of Amphibine analogues showed potency as COVID-19 treatment targeting SARS-CoV-2 Mpro.

IRMOF‐8: Theoretical evaluation of aluminum doping on hydrogen, methane, and hydrogen sulfide adsorption

AbstractThe use of porous materials, aimed at increasing gas storage capacity at lower pressures, exploits physical adsorption and is an emerging strategy that is being widely investigated. In this scope, porous materials such as metal organic frameworks (MOFs) are a viable alternative, where structural modifications can enhance the properties of these materials and improve the degree of adsorption for a given gas. In this work, we evaluated the adsorption of methane, hydrogen, and hydrogen sulfide gases on pure isoreticular MOF (IRMOF)‐8 and aluminum‐doped IRMOF‐8 using density functional theory Perdew‐Burke‐Ernzerhof/DZVP and semiempirical AM1, PM3, PM6, PM6‐DH+, PM6‐DH2, PM6‐D3, and PM7 methods. Adsorption isotherms were calculated by means of Grand Canonical Monte Carlo simulations. It was found that doping did not provide a significant increase in the amount of adsorbed methane and hydrogen gases. Conversely, doping led to a considerable increase for hydrogen sulfide capture.

Molecular Modeling Analyses and Vibrational Characteristics for Nitromethane

Molecular modeling is considered as an effective tool for the evaluation of many physical as well as spectroscopic parameters. In this study semiempirical AM1, PM5, ab initio methods HF and MP2 as well as density functional methods VWN, B88LYP, B88PW91, B3PW91 and B3LYP were used to study nitromethane in its gas phase. The optimized structure, some physical parameters, and vibrational spectrum were calculated and discussed. The calculated optimized structure indicated that nitromethane (NM) belongs to the point group C2V. The obtained data indicated that quantum mixing gives results comparable to both ab initio method in accuracy and semiempirical method in computation time. It is concluded that for a small structure like NM, quantum mixing method provides reliable results in a short computation time. At B3LYP/6-31G(d,p) level, polar solvents showed changes in both HOMO/LUMO band gap energy and molecular electrostatic potential. This is an indication for the stability of NM in different chemical environments.

Isopentyltriphenylphosphonium bromideionic liquid as a newly effective corrosion inhibitor on metal-electrolyte interface in acidic medium: Experimental, surface morphological (SEM-EDX & AFM) and computational analysis

The behavior of mild steel (MS) corrosion in isopentyltriphenylphosphonium bromide (IPTPPB) as a green inhibitor into 0.5 M H2SO4 medium was examined by electrochemical techniques (galvanostatic (GP) and potentiostatic polarizations (PP), and electrochemical impedance spectroscopy (EIS)). Different concentrations of inhibitor were tried; maximum inhibition efficiency (99%) is obtained at 10−2 M IPTPPB in 0.5 M H2SO4. The temperature and adsorption effect was examined by the temperature kinetic study and simulation. The polarization technique explains the mixed type behavior of the inhibitor. The nature of inhibition of MS-IPTPPB was also studied by energy dispersive X-ray spectroscopic (EDXS) technique using surface analysis methods; scanning electron microscopy (SEM) and at atomic force microscopy (AFM). The formation of the monolayer by self-assembly of surfactant molecules at metal surfaces increases the corrosion inhibition ability. Experimental conclusions were found to be consistent with the semi-empirical AM1 method and molecular dynamics (MD) simulation theoretical calculations findings.

QSAR Modeling of Compounds Derived from 1,2,3-Triazolopiperidine as DPP-4 Enzyme Inhibitors Using Semiempirical AM1

<p>This study aims to model the derived compounds of 1,2,3-triazolopiperidine using sem­iempirical method AM1 and determine the further derivation with the better IC<sub>50</sub> values against DPP-4 enzyme theoretically. This research employed ChemDraw Pro 12 software for for 2D struc­tural drawing, Hyperchem 8.0 for 3D modelling, and MLR statistical analysis for modeling QSAR equations. The semiempirical method was likely to be the appropriate platform to apply because the correlation coefficient of H<sup>1 </sup>NMR chemical shift between theoretical and actual value is rela­tively close, 0.8891. The multilinear regression analysis produced 4 equation models where the best one is equation 4 as detailed below:” IC<sub>50</sub> = 875,5116 + (-7400,27*qH35) + (-0,00133* Eat.is) + (-3230,72* qN23) + (3,30277* µ)” n = 25; r<sup>2</sup> = 0,594; <em>Adjusted r<sup>2</sup></em>= 0,486; PRESS = 1,2× 10<sup>4</sup><sup>. </sup>Finally, the theoretically promising substituent was -CN possessing IC<sub>50</sub> value = 1.61 nM. </p>

Accurate prediction of enthalpy of formation combined with AM1 method and molecular descriptors

An error correction model is established by combining the experimental values and the calculated values obtained by the semi-empirical method AM1, and using the multiple stepwise regression (MSR) method on the training set to obtain five descriptors that have a large effect on the error term, and the linear equation of the correction model is derived. The test set is used to verify the reliability of the calibration model. In the training set, the new corrected regression model increased the square of the coefficient of determination (R2) from 0.688 to 0.966 and reduced the root mean square error (RMSE) from 98.563 to 27.249. In the test set, the R2 increased from 0.872 to 0.884, and the RMSE decreased from 43.337 to 37.736. It has good fitting ability and stability. According to the results of multiple stepwise regression, the main atomic structure that causes errors is 〉S==, which indicates that we should take the electrical environment of highly electronegative atoms into consideration, which can provide guidance for accurate calculation of thermodynamic properties.

Quantitative structure activity relationship (qsar) study and biological evaluation on mono-ketone analogs of curcumin as antioxidant

The objective of this study was to design new mono-ketone analogs of curcumin and determine its lipid peroxidation inhibition. Molecular modeling studies were carried out by using the semi-empirical quantum chemical algorithm AM-1 method in MOE 2018.01.01 software. Build QSAR was used to generate an equation model that will be used to design new mono-ketone analogs of curcumin. Synthesis of new compounds produced from an aldol condensation reaction. Thiobarbituric acid reactive substance (TBARS) method was used to determine antioxidant activity by measuring lipid peroxide concentration. Promising predictions values of lipid peroxidation the QSAR study obtained inhibitory activity. The in vitro lipid peroxidation inhibition of 2,6-bis-(3’-ethoxy, 4’-hydroxybenzylidene)-cyclohexanone; 2,6-bis-(3’-Bromo,4’-methoxybenzylidene)-cyclohexanone; and 2,6-bis-(3’,4’-dimethoxybenzylidene)-cyclohexanone indicates good inhibitory with IC50 values of 2.95; 0.95; and 2.45μM respectively. The new mono-ketone analogs of curcumin compound from the QSAR study has been shown to have antioxidant activity by inhibiting lipid peroxidation by scavenging free radicals.

UV Spectrophotometric Determination of Thermodynamic Dissociation Constants of Some Aromatic Hydrazones in Acid Media

The spectral behavior of some p-nitro-p-substituted benzoylhydrazones in the perchloric acid media was followed, applying the UV spectroscopy. The position of the absorption maximum in the spectra was defined in acidic media and the electronic transitions were discussed, as well (7<pH<1). The equilibrium between neutral and protonated form was investigated in the ethanol-water (V/V, 1:1) solutions. The observed changes in the UV spectra suggested that protonation process took place in one step. The pH region of protonation ranges between 1.4 and 2.9. Using the changes in the UV spectra which appear as a result of the protonation reaction the stoichiometric dissociation constants were determined numerically (pKBH+ = n·pH + logI) and graphically (intercept of the dependence of logI on pH). Thermodynamic dissociation constants were estimated as an intercept of dependence of pKBH+ on square root of the ionic strength. In order to achieve that, measurements were performed at different ionic strengths: 0.1, 0.25 and 0.5 mol/dm3, adjusted with sodium perchlorate. The obtained thermodynamic pKBH+ values ranged between 2.07 and 2.58. In order to predict proton transfer at a given pH, semiempirical methods AM1 and PM3 were applied. The influence of the substituents present in the p-position of the benzene ring on pKBH+ values of investigated hydrazones was discussed, too. Total energy, binding energy, enthalpy of formation, Gibbs energies of formation, atomic charge and proton affinity values were used to predict protonation site in hydrazone molecule. Furthermore, the stability and the proton affinity of the isomers (E and Z) in which hydrazones exist and their protonated forms were defined.

Interfacial adsorption behavior of quaternary phosphonium based ionic liquids on metal-electrolyte interface: Electrochemical, surface characterization and computational approaches

In present study two quaternary phosphonium salts namely (1-NapthylMethyl)-triphenylphosphonium Chloride (1-NpMe-TPC) and (4-Methoxybenzyl)-triphenylphosphonium Bromide (4-MeOBz-TPB) are reported as inhibitors for mild steel (MS) corrosion in 0.5MH2SO4 using various electrochemical, theoretical and surface morphological techniques. Inhibitors 1-NpMe-TPC and 4-MeOBz-TPB were prepared by diluting the solution of concentration 10−2 to 10−5M and results are showed maximum efficiencies of 99.72% and 97.76%, respectively at 10−3M concentration (298K). Polarization measurements revealed that both 1-NpMe-TPC and 4-MeOBz-TPB acted as mixed corrosion inhibitors. EIS study revealed that 1-NpMe-TPC and 4-MeOBz-TPB adsorbed at the mild steel/0.5M H2SO4 interfaces and enhanced the magnitude of charge transfer resistances. Adsorption of the 1-NpMe-TPC and 4-MeOBz-TPB at the metallic surface was further supported by SEM and AFM studies. Several thermodynamic parameters (ΔGads0, ΔHads0 and ΔSads0 ), Semi-empirical AM1 and MD parameters were derived in order to describe the adsorption behavior of 1-NpMe-TPC and 4-MeOBz-TPB on metallic surface. The reasonable consistence was found between experimental and theoretical results.

Quantum Chemical Methods for Modeling Covalent Modification of Biological Thiols.

Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular-mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semiempirical and density-functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the prereaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high-exact exchange component, range-separated DFT functionals, and variationally optimized exact exchange (i.e., the LC-B05minV functional) correct this issue to various degrees. The large gradient behavior of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X-D and M06-2X were reasonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06-2X was that molecular dynamics (MD) simulations using this functional were only stable if a fine integration grid was used. The low-cost semiempirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics is not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to methylvinyl ketone was calculated using quantum mechanical/molecular mechanical MD in an explicit polarizable aqueous solvent. © 2019 Wiley Periodicals, Inc.