Electronic properties investigation of human dihydrofolate reductase complexes with ligands

Abstract

Despite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. In the focus of this study are complexes of human dihydrofolate reductase (hDHFR) with a series of known inhibitors bound in the active site. Further, a statistical analysis was performed to establish the relationships between a myriad electronic characteristics and IC₅₀. The change in total volume and the change of own electrons number of hydrogen atoms in their atomic basins are identified as the descriptors correlating the most with the hDHFR inhibition potency. Additionally, two lipophilic parts of protein (Thr56, Ser59, Ile60 and Ile7, Val8, Ala9) were found, which act as a key factor in decreasing bioactivity. The depth analysis of intermolecular interactions showed that the interactions between water molecules and ligand play a crucial role in hDHFR inhibition. Furthermore, the molecular dynamics simulations were used for deeper understanding of the structural inhibition, each for 50 ns time scale in explicit water conditions. Thus, the AlteQ approach made it possible to determine the factors influencing the activity and evaluate them not only qualitatively, but also quantitatively.

Communicated by Ramaswamy H. Sarma

Keywords:

• Electron density
• quantum theory of atoms
• AlteQ approach
• DHFR activity
• DHFR-ligand complexes

Acknowledgment

The authors are very thankful for Taif University researcher supporting project Number TURSP/91, Taif University, Taif, Saudi Arabia.

Disclosure statement

The authors have declared that there is no conflict of interest.

Additional information

Funding

The project was supported by Act 211 Government of the Russian Federation, contract 02.A03.21.0011, and Ministry of Science and Higher Education of the Russian Federation (Grant no – FENU-2020-0019).