PMID- 34060981
OWN - NLM
STAT- MEDLINE
DCOM- 20221216
LR  - 20221221
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
VI  - 40
IP  - 19
DP  - 2022
TI  - A structure-based approach for the discovery of inhibitors against methylcitrate 
      synthase of Paracoccidioides lutzii.
PG  - 9361-9373
LID - 10.1080/07391102.2021.1930584 [doi]
AB  - Paracoccidioidomycosis (PCM) is a systemic mycosis, endemic in Latin America, 
      caused by fungi of the genus Paracoccidioides. The treatment of PCM is complex, 
      requiring a long treatment period, which often results in serious side effects. 
      The aim of this study was to screen for inhibitors of a specific target of the 
      fungus that is absent in humans. Methylcitrate synthase (MCS) is a unique enzyme 
      of microorganisms and is responsible for the synthesis of methylcitrate at the 
      beginning of the propionate degradation pathway. This pathway is essential for 
      several microorganisms, since the accumulation of propionyl-CoA can impair 
      virulence and prevent the development of the pathogen. We performed the modeling 
      and molecular dynamics of the structure of Paracoccidioides lutzii MCS (PlMCS) 
      and performed a virtual screening on 89,415 compounds against the active site of 
      the enzyme. The compounds were selected according to the affinity and efficiency 
      criteria of in vitro tests. Six compounds were able to inhibit the enzymatic 
      activity of recombinant PlMCS but only the compound ZINC08964784 showed 
      fungistatic and fungicidal activity against Paracoccidioides spp. cells. The 
      analysis of the interaction profile of this compound with PlMCS showed its 
      effectiveness in terms of specificity and stability when compared to the 
      substrate (propionyl-CoA) of the enzyme. In addition, this compound did not show 
      cytotoxicity in mammalian cells, with an excellent selectivity index. Our results 
      suggest that the compound ZINC08964784 may become a promising alternative 
      antifungal against Paracoccidioides spp. Communicated by Ramaswamy H. Sarma.
FAU - Lima, Raisa Melo
AU  - Lima RM
AUID- ORCID: 0000-0003-1210-8302
AD  - Molecular Biology Laboratory, Institute of Biological Sciences, Federal 
      University of Goias, Brazil.
AD  - Institute of Tropical Pathology and Public Health, Federal University of Goias, 
      Goiania, Brazil.
FAU - Freitas E Silva, Kleber Santiago
AU  - Freitas E Silva KS
AD  - Molecular Biology Laboratory, Institute of Biological Sciences, Federal 
      University of Goias, Brazil.
FAU - Silva, Livia do Carmo
AU  - Silva LDC
AD  - Institute of Tropical Pathology and Public Health, Federal University of Goias, 
      Goiania, Brazil.
FAU - Ribeiro, Jean Francisco Rosa
AU  - Ribeiro JFR
AD  - Institute of Tropical Pathology and Public Health, Federal University of Goias, 
      Goiania, Brazil.
FAU - Neves, Bruno Junior
AU  - Neves BJ
AD  - Faculty of Pharmacy, Laboratory for Molecular Modeling and Drug Design, Federal 
      University of Goias, Goiania, Brazil.
FAU - Brock, Matthias
AU  - Brock M
AD  - School of Life Science, Fungal Biology Group, University of Nottingham, 
      Nottingham, UK.
FAU - Soares, Celia Maria de Almeida
AU  - Soares CMA
AD  - Molecular Biology Laboratory, Institute of Biological Sciences, Federal 
      University of Goias, Brazil.
FAU - da Silva, Roosevelt Alves
AU  - da Silva RA
AUID- ORCID: 0000-0001-5624-4790
AD  - Collaborative Nucleus of Biosystems, Institute of Exact Sciences, Federal 
      University of Jatai, Jatai, Brazil.
FAU - Pereira, Maristela
AU  - Pereira M
AUID- ORCID: 0000-0002-5482-8036
AD  - Molecular Biology Laboratory, Institute of Biological Sciences, Federal 
      University of Goias, Brazil.
AD  - Institute of Tropical Pathology and Public Health, Federal University of Goias, 
      Goiania, Brazil.
LA  - eng
GR  - MR/N017528/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20210601
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - EC 4.1.3.- (methylcitrate synthase)
RN  - EC 2.3.3.1 (Citrate (si)-Synthase)
RN  - Paracoccidioides lutzii
SB  - IM
MH  - Humans
MH  - Animals
MH  - *Paracoccidioides
MH  - *Paracoccidioidomycosis/drug therapy/microbiology
MH  - Citrate (si)-Synthase/pharmacology
MH  - Mammals
OTO - NOTNLM
OT  - Paracoccidioides spp.
OT  - Virtual screening
OT  - inhibitors
OT  - methylcitrate synthase
OT  - molecular dynamics
EDAT- 2021/06/02 06:00
MHDA- 2022/12/15 06:00
CRDT- 2021/06/01 12:16
PHST- 2021/06/02 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2021/06/01 12:16 [entrez]
AID - 10.1080/07391102.2021.1930584 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2022;40(19):9361-9373. doi: 10.1080/07391102.2021.1930584. 
      Epub 2021 Jun 1.