A DFT-based QSAR study on inhibition of human dihydrofolate reductase

J Mol Graph Model. 2016 Nov:70:23-29. doi: 10.1016/j.jmgm.2016.09.005. Epub 2016 Sep 6.

Abstract

Diaminopyrimidine derivatives are frequently used as inhibitors of human dihydrofolate reductase, for example in treatment of patients whose immune system are affected by human immunodeficiency virus. Forty-seven dicyclic and tricyclic potential inhibitors of human dihydrofolate reductase were analyzed using the quantitative structure-activity analysis supported by DFT-based and DRAGON-based descriptors. The developed model yielded an RMSE deviation of 1.1 a correlation coefficient of 0.81. The prediction set was characterized by R2=0.60 and RMSE=3.59. Factors responsible for inhibition process were identified and discussed. The resulting model was validated via cross validation and Y-scrambling procedure. From the best model, we found several mass-related descriptors and Sanderson electronegativity-related descriptors that have the best correlations with the investigated inhibitory concentration. These descriptors reflect results from QSAR studies based on characteristics of human dihydrofolate reductase inhibitors.

Keywords: DFT; Descriptors; Diaminopyrimidine; Dihydrofolate reductase; QSAR; QSARins.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Folic Acid Antagonists / chemistry*
  • Folic Acid Antagonists / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular*
  • Principal Component Analysis
  • Quantitative Structure-Activity Relationship*
  • Quantum Theory*
  • Static Electricity
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / metabolism*
  • Thermodynamics

Substances

  • Folic Acid Antagonists
  • Tetrahydrofolate Dehydrogenase