New inhibitors of homoserine dehydrogenase from Paracoccidioides brasiliensis presenting antifungal activity

• Published in: Journal of molecular modeling 2019-11, Vol.25 (11), p.325-9, Article 325
• Main Authors: Bueno, Paulo Sérgio Alves, Rodrigues, Franciele Abigail Vilugron, Santos, Jessyka Lima, Canduri, Fernanda, Biavatti, Débora Carina, Pimentel, Arethusa Lobo, Bagatin, Mariane Cristóvão, Kioshima, Érika Seki, de Freitas Gauze, Gisele, Seixas, Flavio Augusto Vicente
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - pharmacology; Cell Line; Cell Line, Tumor; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Chlorocebus aethiops; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Dehydrogenases; Disease control; Fungicides; HeLa Cells; Homoserine Dehydrogenase - antagonists & inhibitors; Humans; Ligands; Microbial Sensitivity Tests - methods; Molecular dynamics; Molecular Dynamics Simulation; Molecular Medicine; Natural products; Original Paper; Paracoccidioides - metabolism; Proteins; Side effects; Stability; Substrates; Theoretical and Computational Chemistry; Toxicity; Vero Cells; Zinc
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-019-4221-2

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 ( Pb HSD) 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 Pb HSD 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.