Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships

González, Jorge Enrique Hernández; Alvarez, Lilian Hernández; Pascutti, Pedro Geraldo; Valiente, Pedro A.

doi:10.1002/prot.25322

Cited by 17 publications

(25 citation statements)

References 84 publications

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“…Replicate MD simulations were also performed when indicated by assigning random initial velocities drawn from a Maxwell-Boltzmann distribution to the atoms during the heating steps. More details concerning the EM protocols, treatment of nonbonded interactions, temperature and pressure control, timestep, etc., can be found elsewhere [44].…”

Section: Molecular Dynamics Simulations Setupmentioning

confidence: 99%

“…ΔG eff values were calculated using the GB-neck2 (GBn2) model available in the MMPBSA.py program [36]. This model was selected as it yielded good correlations with experimental results in a previous work that studied the interaction of FP-2 with peptide-based inhibitor [44]. The method was applied to either trajectories or energy-minimized single structures during rescoring steps, as mentioned earlier.…”

Section: Mm-gbsa Free Energy Calculationsmentioning

confidence: 99%

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In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

González

Salas-Sarduy

Alvarez

et al. 2021

J Comput Aided Mol Des

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Falcipain-2 (FP-2) is a Plasmodium falciparum hemoglobinase widely targeted in the search for antimalarials. FP-2 can be allosterically modulated by various noncompetitive inhibitors that have been serendipitously identified. Moreover, the crystal structures of two inhibitors bound to an allosteric site, termed site 6, of the homolog enzyme human cathepsin K (hCatK) suggest that the equivalent region in FP-2 might play a similar role. Here, we conduct the rational identification of FP-2 inhibitors through virtual screenings (VS) of compounds into several pocket-like conformations of site 6, sampled during molecular dynamics (MD) simulations of the free enzyme. Two noncompetitive inhibitors, ZINC03225317 and ZINC72290660, were confirmed using in vitro enzymatic assays and their poses into site 6 led to calculated binding free energies matching the experimental ones. Our results provide strong evidence about the allosteric inhibition of FP-2 through binding of small molecules to site 6, thus opening the way toward the discovery of new inhibitors against this enzyme.

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Section: Molecular Dynamics Simulations Setupmentioning

confidence: 99%

Section: Mm-gbsa Free Energy Calculationsmentioning

confidence: 99%

In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

González

Salas-Sarduy

Alvarez

et al. 2021

J Comput Aided Mol Des

Self Cite

View full text Add to dashboard Cite

show abstract

“…The year 2017 introduced the first computational study to predict the binding modes of FP-2 inhibitors according to the obtained SAR data of previous studies conducted for peptide inhibitors. The investigators proposed a new strategy to identify the molecular demands of a compound to efficiently bind to FP-2 in one complex [120] . One year later, the same group of investigators identified a promising novel anti-malarial drug (HTS07940).…”

Section: Screening Technology A) Sole Inhibitors For Fpsmentioning

confidence: 99%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

Abaza

2019

Parasitologists United Journal

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“…The literature comprises a large number of inhibitors against FPs derived from both experimental and computational approaches. The identified inhibitors, which are either synthetic or from natural sources, fall into three main categories: peptide-based [31, 54–56], non-peptidic [50, 57–61]; and peptidomimetic [58, 62, 63]. Majority of the peptidic and peptidomimetic inhibitors have shown activity against FPs at nanomolar concentrations.…”

Section: Introductionmentioning

confidence: 99%

Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design

Musyoka

Njuguna

Bishop

2019

Malar J

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Background Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors. Methods Sequence and structure variations between prodomain regions of plasmodial proteins and human cathepsins were determined using in silico approaches. Additionally, evolutionary clustering of these proteins was evaluated using phylogenetic analysis. High quality partial zymogen protein structures were modelled using homology modelling and residue interaction analysis performed between the prodomain segment and mature domain to identify key interacting residues between these two domains. The resulting information was used to determine short peptide sequences which could mimic the inherent regulatory function of the prodomain regions. Through flexible docking, the binding affinity of proposed peptides on the proteins studied was evaluated. Results Sequence, evolutionary and motif analyses showed important differences between plasmodial and human proteins. Residue interaction analysis identified important residues crucial for maintaining prodomain integrity across the different proteins as well as the pro-segment responsible for inhibitory mechanism. Binding affinity of suggested peptides was highly dependent on their residue composition and length. Conclusions Despite the conserved structural and catalytic mechanism between human cathepsins and plasmodial proteases, current work revealed significant differences between the two protein groups which may provide valuable information for selective anti-malarial inhibitor development. Part of this study aimed to design peptide inhibitors based on endogenous inhibitory portions of protease prodomains as a novel aspect. Even though peptide inhibitors may not be practical solutions to malaria at this stage, the approach followed and results offer a promising means to find new malarial inhibitors. Electronic supplementary material The online version of this article (10.1186/s12936-019-2790-2) contains supplementary material, which is available to authorized users.

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Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships

Cited by 17 publications

References 84 publications

In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design

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