Journal of Molecular Modeling

, 25:325 | Cite as

New inhibitors of homoserine dehydrogenase from Paracoccidioides brasiliensis presenting antifungal activity

  • Paulo Sérgio Alves Bueno
  • Franciele Abigail Vilugron Rodrigues
  • Jessyka Lima Santos
  • Fernanda Canduri
  • Débora Carina Biavatti
  • Arethusa Lobo Pimentel
  • Mariane Cristóvão Bagatin
  • Érika Seki Kioshima
  • Gisele de Freitas Gauze
  • Flavio Augusto Vicente SeixasEmail author
Original Paper


Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungi of the genus Paracoccidioides spp., which mainly affects workers in rural regions of Latin America. Although the antifungal agents currently available for the treatment of PCM are effective in controlling the disease, many months are needed for healing, making the side effects and drug interactions relevant. In addition, conventional treatments are not able to control the sequelae left by PCM, even after the cure, justifying the search for new therapeutic options against PCM. In this context, the enzyme homoserine dehydrogenase of P. brasiliensis (PbHSD) was used to screen a library of natural products from the Zinc database using three different docking programs, i.e. Autodock, Molegro, and CLC Drugdiscovery Workbench. Three molecules (Zinc codes 2123137, 15967722, and 20611644) were better ranked than the homoserine substrate (HSE) and were used for in vitro trials of the minimum inhibitory concentration (MIC) and minimal fungicidal concentration (MCF). All three molecules presented a fungicidal profile with MICs/MCFs of 8, 32, and 128 μg mL−1, respectively. The two most promising molecules presented satisfactory results with wide therapeutic ranges in the cytotoxicity assays. Molecular dynamics simulations of PbHSD indicated that the ligands remained bound to the protein by a common mechanism throughout the simulation. The molecule with the lowest MIC value presented the highest number of contacts with the protein. The results presented in this work suggest that the molecule Zinc2123137 may be considered as a hit in the development of new therapeutic options for PCM.


Paracoccidioides brasiliensis Virtual screening Homoserine dehydrogenase Drug discovery 


Funding information

This work was supported by Fundação Araucária (grant number 147/14 and 40/16), Coordination for the Improvement of Higher Education Personnel – Brazil (CAPES, code 001), and National Council for Scientific and Technological Development – Brazil (CNPq grant number 305960/2015-6). The authors thank to LNCC for the computational facilities and FINEP/COMCAP/UEM for the equipment facilities.

Supplementary material

894_2019_4221_MOESM1_ESM.doc (10.6 mb)
ESM 1 (DOC 10821 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Paulo Sérgio Alves Bueno
    • 1
  • Franciele Abigail Vilugron Rodrigues
    • 2
  • Jessyka Lima Santos
    • 3
  • Fernanda Canduri
    • 3
  • Débora Carina Biavatti
    • 1
  • Arethusa Lobo Pimentel
    • 1
  • Mariane Cristóvão Bagatin
    • 4
  • Érika Seki Kioshima
    • 2
  • Gisele de Freitas Gauze
    • 4
  • Flavio Augusto Vicente Seixas
    • 1
    Email author
  1. 1.Department of TechnologyUniversidade Estadual de MaringáUmuaramaBrazil
  2. 2.Department of Clinical Analysis and BiomedicineUniversidade Estadual de MaringáMaringáBrazil
  3. 3.São Carlos Institute of ChemistryUniversidade de São PauloSão CarlosBrazil
  4. 4.Department of ChemistryUniversidade Estadual de MaringáMaringáBrazil

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