In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

Brogi, Simone; Giovani, Simone; Brindisi, Margherita; Gemma, Sandra; Novellino, Ettore; Campiani, Giuseppe; Blackman, Michael J.; Butini, Stefania

doi:10.1016/j.jmgm.2016.01.005

Cited by 19 publications

(19 citation statements)

References 56 publications

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“…None of them contained sub‐structural features that would label them as “frequent hitters” in high‐throughput screens . The three‐dimensional structure of Zmp1 (PDB ID: http://www.rcsb.org/pdb/explore/explore.do?structureId=3ZUK) was taken from the RCSB Protein Data Bank, imported into Maestro, and prepared as described previously …”

Section: Methodsmentioning

confidence: 99%

“…[29] The three-dimensional structure of Zmp1 (PDB ID: 3ZUK) was taken from the RCSB Protein Data Bank, imported into Maestro, and prepared as described previously. [30,31] QM-polarized ligand docking (QPLD), ligand binding energies: Docking studies were performed using the QPLD workflow implemented in Maestro. [18,20] QLPD uses Glide and Qsite software to carry out the calculation for performing docking studies using ab initio methodology to calculate ligand charges within the protein environment, which is essential for charged active sites, such as metalloproteinase.…”

Section: Computational Detailsmentioning

confidence: 99%

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Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

et al. 2018

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The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.

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Section: Methodsmentioning

confidence: 99%

Section: Computational Detailsmentioning

confidence: 99%

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

et al. 2018

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“…The resulting model of gTrxR in complex with NADPH was submitted to a refinement protocol as previously reported by us [42][43][44][45][46] 3.6% in allowed region and 0% of residues in outlier region) of our gTrxR refined model sit in the allowed regions of Ramachandran Plot ( Figure S1). This value is higher than the cut-off value (96.1%) defined for the most reliable models [49,50].…”

Section: Induced Fit Docking (Ifd)mentioning

confidence: 99%

Structural characterization of Giardia duodenalis thioredoxin reductase ( g TrxR) and computational analysis of its interaction with NBDHEX

Brogi¹,

Fiorillo

Chemi³

et al. 2017

European Journal of Medicinal Chemistry

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“…In fact, the consensus sequence of the SUB1 cleavage site, (Val/ Leu/Ile)-Xaa-(Gly/Ala)-Paa, where Xaa represent any amino acid residue and Paa denotes a non-polar residue, except for Leu [27], is well conserved in Group II to IV SERA [17]. SUB1 is also well conserved among Plasmodium species [39].…”

Section: Asexual Blood Stagementioning

confidence: 99%

Characteristic features of the SERA multigene family in the malaria parasite

et al. 2020

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Serine repeat antigen (SERA) is conserved among species of the genus Plasmodium. Sera genes form a multigene family and are generally tandemly clustered on a single chromosome. Although all Plasmodium species encode multiple sera genes, the number varies between species. Among species, the members share similar sequences and gene organization. SERA possess a central papain-like cysteine protease domain, however, in some members, the active site cysteine residue is substituted with a serine. Recent studies implicate this gene family in a number of aspects in parasite biology and induction of protective immune response. This review summarizes the current understanding on this important gene family in several Plasmodium species. The Plasmodium falciparum (Pf)-sera family, for example, consists of nine gene members. Unlike other multigene families in Plasmodium species, Pf-sera genes do not exhibit antigenic variation. Pf-sera5 nucleotide diversity is also low. Moreover, although Pf-sera5 is highly transcribed during the blood stage of malaria infection, and a large amount is released into the host blood following schizont rupture, in malaria endemic countries the sero-positive rates for Pf-SERA5 are low, likely due to Pf-SERA5 binding of host proteins to avoid immune recognition. As an antigen, the N-terminal 47 kDa domain of Pf-SERA5 is a promising vaccine candidate currently undergoing clinical trials. Pf-SERA5 and Pf-SERA6, as well as P. berghei (Pb)-SERA3, and Pb-SERA5, have been investigated for their roles in parasite egress. Two P. yoelii SERA, which have a serine residue at the protease active center, are implicated in parasite virulence. Overall, these studies provide insight that during the evolution of the Plasmodium parasite, the sera gene family members have increased by gene duplication, and acquired various functions that enable the parasite to survive and successfully maintain infection in the host.

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In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

Abstract: Graphical abstract

Cited by 19 publications

References 56 publications

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

Structural characterization of Giardia duodenalis thioredoxin reductase ( g TrxR) and computational analysis of its interaction with NBDHEX

Characteristic features of the SERA multigene family in the malaria parasite

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