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Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy.

ABSTRACT: Background:Lung cancer is the leading cause of cancer-related death worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) is the most common. Recently, the mitochondrial isoform of the enzyme phosphoenolpyruvate carboxykinase (HsPEPCK-M) was identified as responsible for the metabolic adaptation in the NSCLC allowing tumor growth even under conditions of glucose deficiency. This adaptation is possible due to the role of HsPEPCK-M in gluconeogenesis, converting the oxaloacetate to phosphoenolpyruvate in the presence of GTP, which plays an important role in the energetic support of these tumors. In this context, it was shown that the inhibition or knockdown of this enzyme was able to induce apoptosis in NSCLC under low glucose conditions. Purpose:In this study, novel putative inhibitors were proposed for the human PEPCK-M (HsPEPCK-M) based on a computer-aided approach. Methods:Comparative modeling was used to generate 3D models for HsPEPCK-M. Subsequently, the set of natural compounds of the ZINC database was screened against HsPEPCK-M models using structure-based pharmacophore modeling and molecular docking approaches. The selected compounds were evaluated according to its chemical diversity and clustered based on chemical similarity. Results:The pharmacophore hypotheses, generated based on known PEPCK inhibitors, were able to select 7,124 candidate compounds. These compounds were submitted to molecular docking studies using three conformations of HsPEPCK-M generated by comparative modeling. The aim was to select compounds with high predicted binding affinity for at least one of the conformations of HsPEPCK-M. After molecular docking, 612 molecules were selected as potential inhibitors of HsPEPCK-M. These compounds were clustered according to their structural similarity. Chemical profiling and binding mode analyses of these compounds allowed the proposal of four promising compounds: ZINC01656421, ZINC895296, ZINC00895535 and ZINC02571340. Conclusion:These compounds may be considered as potential candidates for HsPEPCK-M inhibitors and may also be used as lead compounds for the development of novel HsPEPCK-M inhibitors.

SUBMITTER: Baptista LPR

PROVIDER: S-EPMC6689533 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy.

Baptista Luiz Phillippe R LPR Sinatti Vanessa Vc VV Da Silva Joao Hm JH Dardenne Laurent Emmanuel LE Guimarães Ana Carolina AC

Advances and applications in bioinformatics and chemistry : AABC 20190807

<h4>Background</h4>Lung cancer is the leading cause of cancer-related death worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) is the most common. Recently, the mitochondrial isoform of the enzyme phosphoenolpyruvate carboxykinase (HsPEPCK-M) was identified as responsible for the metabolic adaptation in the NSCLC allowing tumor growth even under conditions of glucose deficiency. This adaptation is possible due to the role of HsPEPCK-M in gluconeogenesis, converting the oxaloacetat ...[more]

PMID: 31496750

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Project description:Ebola virus (EBOV) is one of the most lethal pathogens that can infect humans. The Ebola viral protein VP35 (EBOV VP35) inhibits host IFN-α/β production by interfering with host immune responses to viral invasion and is thus considered as a plausible drug target. The aim of this study was to identify potential novel lead compounds against EBOV VP35 using computational techniques in drug discovery. The 3D structure of the EBOV VP35 with PDB ID: 3FKE was used for molecular docking studies. An integrated library of 7675 African natural product was pre-filtered using ADMET risk, with a threshold of 7 and, as a result, 1470 ligands were obtained for the downstream molecular docking using AutoDock Vina, after an energy minimization of the protein via GROMACS. Five known inhibitors, namely, amodiaquine, chloroquine, gossypetin, taxifolin and EGCG were used as standard control compounds for this study. The area under the curve (AUC) value, evaluating the docking protocol obtained from the receiver operating characteristic (ROC) curve, generated was 0.72, which was considered to be acceptable. The four identified potential lead compounds of NANPDB4048, NANPDB2412, ZINC000095486250 and NANPDB2476 had binding affinities of -8.2, -8.2, -8.1 and -8.0 kcal/mol, respectively, and were predicted to possess desirable antiviral activity including the inhibition of RNA synthesis and membrane permeability, with the probable activity (Pa) being greater than the probable inactivity (Pi) values. The predicted anti-EBOV inhibition efficiency values (IC50), found using a random forest classifier, ranged from 3.35 to 11.99 μM, while the Ki values ranged from 0.97 to 1.37 μM. The compounds NANPDB4048 and NANPDB2412 had the lowest binding energy of -8.2 kcal/mol, implying a higher binding affinity to EBOV VP35 which was greater than those of the known inhibitors. The compounds were predicted to possess a low toxicity risk and to possess reasonably good pharmacological profiles. Molecular dynamics (MD) simulations of the protein-ligand complexes, lasting 50 ns, and molecular mechanisms Poisson-Boltzmann surface area (MM-PBSA) calculations corroborated the binding affinities of the identified compounds and identified novel critical interacting residues. The antiviral potential of the molecules could be confirmed experimentally, while the scaffolds could be optimized for the design of future novel anti-EBOV chemotherapeutics.

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Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy.

Publications

Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy.

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