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Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1674–1682 | Cite as

Structure-based lead optimization to improve the antifungal potency of the tetrahydroimidazo pyridine inhibitors targeted to Candida albicans dihydrofolate reductase and lanosterol 14-alpha-demethylase

  • Srimai Vuppala
  • Ramesh Kumar Chitumalla
  • Bo Sun JooEmail author
  • Joonkyung JangEmail author
Original Research
  • 83 Downloads

Abstract

We investigate the binding and inhibition profiles for a selected dataset of tetrahydroimidazo pyridine molecules against Candida albicans dihydrofolate reductase (DHFR) and lanosterol 14-alpha-demethylase (CYP51). A hit molecule was screened and identified through Lipinski’s rule of five, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and the molecular docking. Some inhibitors of our design have shown positive drug scores, good solubilities, and high docking scores over the selected dataset. The first-principles calculation based on the density functional theory was carried out to understand how the electronic distributions of frontier orbitals of molecules affect their inhibition profiles. The present structure-based approach enabled us to design new pharmacophore analogs with improved ADMET profile, drug scores, and docking scores against selected receptors.

Keywords

Density functional theory Structure-based lead optimization Candida albicans dihydrofolate reductase Lanosterol 14-alpha-demethylase Molecular docking ADMET 

Notes

Acknowledgements

This study was supported by the National Research Foundation Grants funded by the Korean Government (2018R1A2A2A05019776).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2404_MOESM1_ESM.docx (123 kb)
Supplementary Material.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nanoenergy EngineeringPusan National UniversityBusanRepublic of Korea
  2. 2.Infertility InstitutePohang Women’s HospitalPohangRepublic of Korea

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