Computational study on the mechanisms of inhibition of SARS-CoV-2 Mpro by aldehyde warheads based on DFT.

SARS-CoV-2 main protease, Mpro, plays a crucial role in the virus replication cycle, making it an important target for antiviral research. In this study, a simplified model obtained through truncation is used to explore the reaction mechanism of aldehyde warhead compounds inhibiting Mpro at the level of density functional theory. According to the calculation results, proton transfer (P_T)-nucleophilic attack (N_A) is the rate-determining step in the entire reaction pathway. The water molecule that plays a catalytic role occupies the oxyanion hole, which is unfavorable for the aldehyde warhead to approach the Cys145 SH. Through a hypothetical study of substituting the main chain NH with methylene, it is further confirmed that the P_T-N_A is a proton transfer-dominated process accompanied by a nucleophilic attack reaction. In this process, the oxyanion hole serves only to stabilize the aldehyde oxygen anion and therefore does not have a significant impact on the activation free energy barrier of the step. Our research results provide a unique perspective for understanding the covalent inhibition reaction of the Mpro active site. This study also offers theoretical guidance for the design of new Mpro covalent inhibitors.

Computational Mechanism Investigation of C=C Bond Hydrogenation Catalyzed by Rhodium Hydride.

The hydrogenation of unsaturated carbons is a commonly used synthetic tool in pharmaceutical and industrial production. Recently, the Norton group realized highly selective hydrogenation of C=C bonds catalyzed by a rhodium hydride. Despite the great efforts made by experimentalists, details regarding the mechanism remained unclear. In this work, detailed DFT calculations were carried out to elucidate the principal features of this transformation. For enones we find that two possible competing mechanisms proposed by the experimental groups are computationally excluded, our proposed alternative mechanism with a total barrier of 20.0 kcal mol-1 is theoretically feasible, solvent methanol to also plays a crucial role in assisting ß-hydrogenation in addition to being the hydrogen source for α-hydrogenation, and the cross-polarization of the substrate enone-conjugated system to result in an enhanced charge density of the α-carbon, which favors being hydrogenated first. For isolated alkenes, neither of the two possible competing mechanisms can be excluded computationally and which carbon atom is first hydrogenated depends on the electronic properties of the substrate itself. The combination of rhodium and C=C bonds changes the electronic properties of H on the rhodium hydride and enhances its hydrogenation activity.

Mechanism of Direct C-H Arylation of Pyridine via a Transient Activator Strategy: A Combined Computational and Experimental Study.

Recently, we realized the highly selective one-pot synthesis of 2,6-diarylpyridines by using a Pd-catalyzed direct C-H arylation approach via a transient activator strategy. Although methylation reagent as a transient activator and Cu(I) salt or oxide were found to be prerequisites, details regarding the mechanism remained unclear. In this paper, DFT calculations combined with experimental investigations were carried out to elucidate the principle features of this transformation. The results reveal (1) the origin of the exquisite diarylating selectivity of the pyridine under the transient strategy; (2) the possible demethylating reagent as the counteranion of the pyridinium salt; (3) the reason why Cu2O is a better Cu(I) resource than others.

[The Study on Infrared Spectra of 7-Hydroxycoumarin by Density Functional Theory].

Infrared spectroscopy is an important source of information for the identification of the compounds structure and it is great significant for biological activity research of natural and organic drug molecules. With the theoretical calculation method is more reasonable and calculation accuracy continues to improve, Theoretical calculate advantage is more obvious in the infrared spectrum simulation and vibration modes attributable identified. And it has important reference value for experimental study of infrared spectral analysis. Using density functional theory, geometry optimizations and frequencies calculation of 7-Hydroxycoumarin were performed at the level of B3LYP/6-311G(d, p), the stable structure and all vibration modes of 7-Hydroxycoumarin were attained. The results show that the infrared absorption peak of 7-hydroxycoumarin is mainly distributed in the several regions in wave number of 3 700-3 500, 3 150-3 000, 1 750-1 400, 1 400-1 000, 1 000-50 cm(-1). In addition to the vibration in a wave number range of 3 700-3 500, 3 150-3 000 cm(-1) is relatively independent, and were attributed to OH stretching vibration and benzene ring CH stretching vibration, the other several vibration regions are more complex, the different degree of spectral peaks is composed of multiple vibration modes. Finally, based on the theoretical analysis of the vibration mode, the vibration modes of 7-Hydroxycoumarin molecule were assigned, and in order to discuss the reliability of theoretical calculation method, the correlation diagram of the main absorption peak of 7-hydroxyl group was drawn from the theoretical value of X axis and the experimental value of Y axis, the correlation between experimental IR data and calculated IR data of 7-Hydroxycoumarin was analyzed through the linear regression method. Results show that they have good correlation, correlation coefficient values "r" equals 0.998 5, and the theory calculation of 7-Hydroxycoumarin IR by density functional theory at the base set level is reliable.

[Theoretical study on fluorescence spectra of four kinds of p-substituted curcumin analogues].

Four kinds of p-substituted curcumin analogues were optimized at B3LYP/6-31G (d, p) level. On this basis, the excited states geometry structure was optimized by the CIS method, and finally the fluorescence emission spectra were calculated through the TD-DFT method. The results showed that: the four compounds, a large conjugated system, is preferably coplanar structure. Because of introducing hydroxyl and halogen atom on the benzene ring, the molecular pi-electron conjugation is relatively larger, emission wavelength is relatively longer, and fluorescence spectra show different degrees of red shift. As the electron donating group is hydroxy, the fluorescence phenomenon is more obviously red shifted.

[Theoretical study on nuclear magnetic resonance spectra of the four kinds of curcumin analogues].

Abstract The structure of four kinds of curcumin analogues was optimized at the level of B3LYP/6-31G(d, p), under which the stability was verified by means of vibration analysis. Moreover, NMR spectra of urcumin analogues compounds were studied at the level of B3LYP/6-311G(d,p) by GIAO method. The results show that the structure of four kinds of compounds, a larger conjugated system, has good planarity. Because of introducing hydroxyl and methoxy, the compound-B/C/D-C3, C4 and compoud-A and compound-D-Cs have greater 8 value. delta value of compound-A-C4. C4 is relatively smaller, and delta value of C3 is relatively larger. In the conjugated carbonyl compounds, compared with the acetaldehyde delta value (201 ppm), carbonyl C13 delta value (183 ppm) decreases relatively, C(11, 15) (alpha-carbon) delta value(122 ppm) decreases relatively, and C(9, 17) (beta-carbon) delta value(145 ppm) increases relatively. Finally, the correlation between experimental delta value and theoretical delta value of the 1H NMR was analyzed through the linear regression method. Results show that they have good correlation, and the experimental values coincide with the theoretical values.