A computer-aided method for controlling chemical resistance of drugs using RRKM theory in the liquid phase

Abstract

The chemical resistance of drugs against any change in their composition and studying the rate of multiwell-multichannel reactions in the liquid phase, respectively, are the important challenges of pharmacology and chemistry. In this article, we investigate two challenges together through studying drug stability against its unimolecular reactions in the liquid phase. Accordingly, multiwell-multichannel reactions based on 1,4-H shifts are designed for simplified drugs such as 3-hydroxyl-1H-pyrrol-2(5H)-one, 3-hydroxyfuran-2(5H)-one, and 3-hydroxythiophen-2(5H)-one. After that, the reverse and forward rate constants are calculated by using the Rice Ramsperger Kassel Marcus theory (RRKM) and Eckart tunneling correction over the 298–360 K temperature range. Eventually, using the obtained rate constants, we can judge drug resistance versus structural changes. To attain the goals, the potential energy surfaces of all reactions are computed by the complete basis set-quadratic Becke3 composite method, CBS-QB3, and the high-performance meta hybrid density functional method, M06-2X, along with the universal Solvation Model based on solute electron Density, SMD, due to providing more precise and efficient results for the barrier heights and thermodynamic studies. To find the main reaction pathway of the intramolecular 1,4-H shifts in the target molecules, all possible reaction pathways are considered mechanistically in the liquid phase. Also, the direct dynamics calculations that carry out by RRKM theory on the modeled pathways are used to distinguish the main reaction pathway. As the main finding of this research, the results of quantum chemical calculations accompanied by the RRKM/Eckart rate constants are used to predict the stability of drugs. This study proposes a new way to examine drug stability by the computer-aided reaction design of target drugs. Our results show that 3-hydroxyfuran-2(5H)-one based drugs are the most stable and 3-hydroxythiophen-2(5H)-one based drugs are more stable than 3-hydroxy-1H-pyrrol-2 (5H)-one based drugs in water solution.

PubChemQC B3LYP/6-31G*//PM6 Data Set: The Electronic Structures of 86 Million Molecules Using B3LYP/6-31G* Calculations

“…Including quantum chemical calculations 25−28 can substantially increase the utility of diverse molecular databases. In the field of drug discovery, for instance, quantum chemical calculations can aid in studying molecular interactions, 29 identifying new drug targets, designing novel drug molecules, 30 understanding reaction mechanisms, 31−34 analyzing drug stability, 35 developing more reliable QSAR (Quantitative Structure−Activity Relationship) models, 36−38 and drug metabolism, 39,40 other hand, a wider HOMO−LUMO energy gap favors nonfluorescent mechanisms such as triplet−triplet upconversion. Therefore, it is essential to consider the HOMO−LUMO energy gap when designing and refining electroluminescent materials.…”

“…Including quantum chemical calculations − can substantially increase the utility of diverse molecular databases. In the field of drug discovery, for instance, quantum chemical calculations can aid in studying molecular interactions, identifying new drug targets, designing novel drug molecules, understanding reaction mechanisms, − analyzing drug stability, developing more reliable QSAR (Quantitative Structure–Activity Relationship) models, − and drug metabolism, , among other applications. In the context of organic light-emitting diode (OLED) materials, the Highest Occupied Molecular Orbital (HOMO) energy minus the Lowest Unoccupied Molecular Orbital (LUMO) energy, or the HOMO–LUMO energy gap, plays a crucial role in determining their optoelectronic properties.…”

A Comparative Study of Cosmo-Based and Equation-of-State Approaches for the Prediction of Solvation Energies Based on the Compsol Databank

“…Given that this thermodynamic quantity is related to the degree of affinity between different chemical species, it can be very useful, for example, in the selection of an adequate solvent for a separation process or a chemical reaction. The computation of solvation quantities is also a critical matter in pharmacology and drug-design, since the solvation phenomena directly affects the affinity of a given biologically active substance for target proteins, as well as its solubility and chemical stability [1][2][3][4].…”