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DNA polymerase η (polη) is of significant value for designing new families of anticancer drugs. This protein takes a role in many stages of the cell cycle, including DNA replication, translesion DNA synthesis, and the repairing process of DNA. According to many studies, a high level of expression of polη in most cases has been associated with low rates of patients' survival, regardless of considering the stage of tumor cells. Thus, the design of new drugs with fewer side effects to inhibit polη in cancerous cells has attracted attention in recent years. This project aims to design and explore the alternative inhibitors for polη, which are based on carbohydrates and amino acids. In terms of physicochemical properties, they are similar to the traditional anticancer drugs such as Cytarabine (cytosine arabinose). These alternative inhibitors are supposed to disrupt the DNA replication process in cancerous cells and prevent the tumor cells from mitosis. These newly designed structures, which are based on natural products, are expected to be non-toxic and to have the same chemotherapeutic impact as the traditional agents. The combinatorial use of quantum mechanics studies and molecular dynamic simulation has enabled us to precisely predict the inhibition mechanism of the newly designed structure, which is based on carbohydrates and amino acids, and compare it with that of the traditional chemotherapeutic drugs such as Cytarabine. Our results suggest that the inhibitors containing the natural building blocks of amino acid and carbohydrate could be considered alternative drugs for Cytarabine to block polη., (© 2022. The Author(s).)

The interactions between five amino acid based anions ([AA](-) (AA = Gly, Phe, His, Try, and Tyr)) and N7,N9-dimethylguaninium cation ([dMG](+)) have been investigated by the hybrid density functional theory method B3LYP together with the basis set 6-311++G(d,p). The calculated interaction energy was found to decrease in magnitude with increasing side-chain length in the amino acid anion. The interaction between the [dMG](+) cation and [AA](-) anion in the most stable configurations of ion pairs is a hydrogen bonding interaction. These hydrogen bonds (H bonds) were analyzed by the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. Finally, several correlations between electron densities in bond critical points of hydrogen bonds and interaction energy as well as vibrational frequencies in the most stable configurations of ion pairs have been checked.

B3LYP/aug-cc-pVDZ computations were carried out on polyamines with up to seven amino groups. The gas-phase proton affinities of these compounds are 219.6 (1-BuNH2), 238.6 (H2NCH2CH2CH2CH2NH2), 252.8 [(H2NCH2CH2CH2)2CHNH2], 261.3 [(H2NCH2CH2CH2)3CNH2 (1)], and 288.5 kcal mol-1 [(H2NCH2CH2CH(NH2)CH2CH2)3CNH2]. These results indicate that the tetraamine is near the top of the basicity scale and the heptaamine is more basic than any neutral organic compound which has been measured to date. A gas-phase equilibrium acidity determination between 1 and DBU also was carried out, and PA(1) = 256.2 ± 2.1 kcal mol-1 was obtained. This demonstrates that multiple intramolecular hydrogen bonds can greatly increase basicities, and represents a new motif for designing super bases. [ABSTRACT FROM AUTHOR]