PMID- 31244810
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1664-302X (Print)
IS  - 1664-302X (Electronic)
IS  - 1664-302X (Linking)
VI  - 10
DP  - 2019
TI  - Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics 
      Framework.
PG  - 1301
LID - 10.3389/fmicb.2019.01301 [doi]
LID - 1301
AB  - Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin 
      America. The disease is caused by fungi of the genus Paracoccidioides and mainly 
      affects low-income rural workers after inhalation of fungal conidia suspended in 
      the air. The current arsenal of chemotherapeutic agents requires long-term 
      administration protocols. In addition, chemotherapy is related to a significantly 
      increased frequency of disease relapse, high toxicity, and incomplete elimination 
      of the fungus. Due to the limitations of current anti-PCM drugs, we developed a 
      computational drug repurposing-chemogenomics approach to identify approved drugs 
      or drug candidates in clinical trials with anti-PCM activity. In contrast to the 
      one-drug-one-target paradigm, our chemogenomics approach attempts to predict 
      interactions between drugs, and Paracoccidioides protein targets. To achieve this 
      goal, we designed a workflow with the following steps: (a) compilation and 
      preparation of Paracoccidioides spp. genome data; (b) identification of 
      orthologous proteins among the isolates; (c) identification of homologous 
      proteins in publicly available drug-target databases; (d) selection of 
      Paracoccidioides essential targets using validated genes from Saccharomyces 
      cerevisiae; (e) homology modeling and molecular docking studies; and (f) 
      experimental validation of selected candidates. We prioritized 14 compounds. Two 
      antineoplastic drug candidates (vistusertib and BGT-226) predicted to be 
      inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at 
      low micromolar concentrations (<10 muM). Four antifungal azole drugs (bifonazole, 
      luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low 
      nanomolar concentrations, validating our methodology. The results suggest our 
      strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend 
      hit-to-lead optimization studies to improve potency and selectivity, as well as 
      pharmaceutical formulations to improve oral bioavailability of the antifungal 
      azoles identified.
FAU - de Oliveira, Amanda Alves
AU  - de Oliveira AA
AD  - Laboratorio de Biologia Molecular, Universidade Federal de Goias, Goiania, 
      Brazil.
AD  - Laboratorio de Cheminformatica, Centro Universitario de Anapolis, UniEVANGELICA, 
      Anapolis, Brazil.
FAU - Neves, Bruno Junior
AU  - Neves BJ
AD  - Laboratorio de Cheminformatica, Centro Universitario de Anapolis, UniEVANGELICA, 
      Anapolis, Brazil.
FAU - Silva, Livia do Carmo
AU  - Silva LDC
AD  - Laboratorio de Biologia Molecular, Universidade Federal de Goias, Goiania, 
      Brazil.
FAU - Soares, Celia Maria de Almeida
AU  - Soares CMA
AD  - Laboratorio de Biologia Molecular, Universidade Federal de Goias, Goiania, 
      Brazil.
FAU - Andrade, Carolina Horta
AU  - Andrade CH
AD  - Laboratorio de Modelagem Molecular e Design de Medicamentos, Faculdade de 
      Farmacia, Universidade Federal de Goias, Goiania, Brazil.
FAU - Pereira, Maristela
AU  - Pereira M
AD  - Laboratorio de Biologia Molecular, Universidade Federal de Goias, Goiania, 
      Brazil.
LA  - eng
PT  - Journal Article
DEP - 20190612
PL  - Switzerland
TA  - Front Microbiol
JT  - Frontiers in microbiology
JID - 101548977
PMC - PMC6581699
OTO - NOTNLM
OT  - Paracoccidioides species
OT  - drug repurposing
OT  - gene essentiality
OT  - genome-wide alignment
OT  - in vitro assays
OT  - molecular docking
EDAT- 2019/06/28 06:00
MHDA- 2019/06/28 06:01
PMCR- 2019/06/12
CRDT- 2019/06/28 06:00
PHST- 2019/02/11 00:00 [received]
PHST- 2019/05/24 00:00 [accepted]
PHST- 2019/06/28 06:00 [entrez]
PHST- 2019/06/28 06:00 [pubmed]
PHST- 2019/06/28 06:01 [medline]
PHST- 2019/06/12 00:00 [pmc-release]
AID - 10.3389/fmicb.2019.01301 [doi]
PST - epublish
SO  - Front Microbiol. 2019 Jun 12;10:1301. doi: 10.3389/fmicb.2019.01301. eCollection 
      2019.