The new approach based on MD studies to design novel anticancer drugs based on amino acids and carbohydrates to inhibit DHFR

DHFR is one of the essential enzymes in the Thymidylate synthesis cycle. The expression of this enzyme intumor cells and some related autoimmune diseases such as Psoriasis, which is a derma-related illness, hasbeen observed. The inhibition of this enzyme will lead to suppressing the production of ۵,۱۰-Methylenetetrahydrofolate in cells. ۵,۱۰-Methylenetetrahydrofolate is produced from tetrahydrofolate withthe aid of SHMT. As a result, the mentioned inhibition will cause cell death.Methotrexate is one of the drugs for treating Psoriasis, which has many side effects such as intestinalproblems, respiratory disorders, blood disorders, central nervous system disorders, and elevated liverfunction.This project aims to replace Methotrexate with drugs based on carbohydrates and amino acid blocks withfewer side effects.To achieve our goals in designing new drugs, we employ quantum mechanics and molecular dynamicmethods. Firstly, concerning the main drug structure (Methotrexate), some new structures based on aminoacids and carbohydrates will be suggested. Then, the newly designed structures will be optimized at theDFT/rB۳LYP/۶-۳۱G+(d) level. It should be noted that the primary conformer search of the structures will becarried out using Spartan software. Following that, Autodock and Autodock/vina are the software used toselect the best replacements. Outputs of the docking procedures will be used for molecular dynamicssimulations. Furthermore, the energy analyses for this study will be performed by MM/PBSA method. Wehope that the results of this study will lead to the design of more effective and less toxic anticancer and antiautoimmunedrugs.

Keywords:

Inhibitor , Drug design , Computational design , Anti-cancer compounds , Sugar and amino acid , Methotrexate