Role of π-conjugation on the coordination behaviour, substitution kinetics, DNA/BSA interactions, and <i>in vitro</i> cytotoxicity of carboxamide palladium(<scp>ii</scp>) complexes

Omondi, Reinner O.; Sibuyi, Nicole Remaliah Samantha; Fadaka, Adewale Oluwaseun; Meyer, Mervin; Jaganyi, Deogratius; Ojwach, Stephen O.

doi:10.1039/d1dt00412c

Cited by 17 publications

(12 citation statements)

References 64 publications

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“…The RMSD was used to judge whether the AKT1 complex system reaches equilibrium during the simulation process. Generally, a smaller RMSD value indicates a more stable system ( 37 ). As shown in Figure 14C , the RMSD curve fluctuated around 2.7Å and the amplitude remained within 3.5 Å, indicating that the AKT1-NaB complex system was stable and the bond was firm.…”

Section: Resultsmentioning

confidence: 99%

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

et al. 2022

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BackgroundRadiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments.MethodsThe predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB.ResultsA total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway.ConclusionsNaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.

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Section: Resultsmentioning

confidence: 99%

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

et al. 2022

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“…The obtained RMSD values ranged from 1.81 ± 0.30 to 3.05 ± 0.57 Å. Rutin had the lowest RMSD (1.81 ± 0.30 Å) followed by Quercetin-3-O-Neohesperidoside with RMSD of 1.98 ± 0.19 Å. The lower the RMSD the less deviation from the backbone and the greater the stability [57]. The stability of these compounds is in the order of Rutin > Quercetin-3-O-Neohesperidoside > Quercetin 3-Rhamnoside > Myricetin 3-Rutinoside > Myricitrin.…”

Section: Molecular Dynamic Simulationmentioning

confidence: 98%

Development of Effective Therapeutic Molecule from Natural Sources against Coronavirus Protease

Fadaka

Sibuyi

Martin

et al. 2021

IJMS

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The SARS-CoV-2 main protease (Mpro) is one of the molecular targets for drug design. Effective vaccines have been identified as a long-term solution but the rate at which they are being administered is slow in several countries, and mutations of SARS-CoV-2 could render them less effective. Moreover, remdesivir seems to work only with some types of COVID-19 patients. Hence, the continuous investigation of new treatments for this disease is pivotal. This study investigated the inhibitory role of natural products against SARS-CoV-2 Mpro as repurposable agents in the treatment of coronavirus disease 2019 (COVID-19). Through in silico approach, selected flavonoids were docked into the active site of Mpro. The free energies of the ligands complexed with Mpro were computationally estimated using the molecular mechanics-generalized Born surface area (MM/GBSA) method. In addition, the inhibition process of SARS-CoV-2 Mpro with these ligands was simulated at 100 ns in order to uncover the dynamic behavior and complex stability. The docking results showed that the selected flavonoids exhibited good poses in the binding domain of Mpro. The amino acid residues involved in the binding of the selected ligands correlated well with the residues involved with the mechanism-based inhibitor (N3) and the docking score of Quercetin-3-O-Neohesperidoside (−16.8 Kcal/mol) ranked efficiently with this inhibitor (−16.5 Kcal/mol). In addition, single-structure MM/GBSA rescoring method showed that Quercetin-3-O-Neohesperidoside (−87.60 Kcal/mol) is more energetically favored than N3 (−80.88 Kcal/mol) and other ligands (Myricetin 3-Rutinoside (−87.50 Kcal/mol), Quercetin 3-Rhamnoside (−80.17 Kcal/mol), Rutin (−58.98 Kcal/mol), and Myricitrin (−49.22 Kcal/mol). The molecular dynamics simulation (MDs) pinpointed the stability of these complexes over the course of 100 ns with reduced RMSD and RMSF. Based on the docking results and energy calculation, together with the RMSD of 1.98 ± 0.19 Å and RMSF of 1.00 ± 0.51 Å, Quercetin-3-O-Neohesperidoside is a better inhibitor of Mpro compared to N3 and other selected ligands and can be repurposed as a drug candidate for the treatment of COVID-19. In addition, this study demonstrated that in silico docking, free energy calculations, and MDs, respectively, are applicable to estimating the interaction, energetics, and dynamic behavior of molecular targets by natural products and can be used to direct the development of novel target function modulators.

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“…In addition, the relatively low kinetic reactivity of the complexes (k 2 ∼ magnitude 10 2 ) could account for their lower cytotoxic effects, since some degree of kinetic reactivity is required for the drug to reach the DNA target [60]. From our previous studies Pd(II) complexes with k 2 values ranging from 10 3 to 10 4 displayed better cytotoxic potency comparable to cisplatin [18,61].…”

Section: In Vitro Cytotoxicity Assaymentioning

confidence: 99%

Synthesis, substitution kinetics, DNA/BSA binding and cytotoxicity of tridentate N^E^N (E = NH, O, S) pyrazolyl palladium(II) complexes

Omondi

Fadaka²,

Fatokun³

et al. 2022

J Biol Inorg Chem

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The pincer complexes, [Pd(L 1 )Cl]BF 4 (PdL 1 ), [Pd(L 2 )Cl]BF 4 (PdL 2 ), [Pd(L 3 )Cl]BF 4 (PdL 3 ), [Pd(L 4 )Cl]BF 4 (PdL 4 ) were prepared by reacting the corresponding ligands, 2,6-bis[(1H-pyrazol-1-yl)methyl]pyridine (L 1 ), bis[2-(1H-pyrazol-1-yl)ethyl] amine (L 2 ), bis[2-(1H-pyrazol-1-yl)ethyl]ether (L 3 ), and bis[2-(1H-prazol-1-yl)ethyl]sulphide (L 4 ) with [PdCl 2 (NCMe)] 2 in the presence NaBF 4 . The solid-state structures of complexes PdL 1 -PdL 4 confirmed a tridentate coordination mode,with one chloro ligand completing the coordination sphere to afford square-planar complexes. Chemical behaviour of the complexes in solution confirms their stability in both aqueous and DMSO stock media. The electrochemical properties of the compounds showed irreversible two-electron reduction process. Kinetic reactivity of Pd complexes with the biological nucleophiles viz, thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5'-GMP) followed the order: PdL 2 < PdL 3 < PdL 4 , and PdL 2 < PdL 1 . The kinetic reactivity is subject to the electronic effects of the spectator ligand(s), and the trend was supported by the DFT computed results. The palladium complexes PdL 1 -PdL 4 bind to calf thymus (CT-DNA) via intercalation mode. In addition, the bovine serum albumin (BSA) showed good binding affinity to the complexes. The mode of quenching mechanism of the intrinsic fluorescence of CT-DNA and BSA by the complexes was found to be static. The order of interactions of the complexes with DNA and BSA was in tandem with the rate of substitution kinetics. The complexes, however, displayed relatively low cytotoxicity (IC 50 > 100 µM) when tested against the human cervical adenocarcinoma (HeLa) cell line and the transformed human lung fibroblast cell line (MRC-5 SV2).

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Role of π-conjugation on the coordination behaviour, substitution kinetics, DNA/BSA interactions, and in vitro cytotoxicity of carboxamide palladium(ii) complexes

Abstract: The coordination chemistry of four carboxamide palladium(ii) complexes, their substitution kinetics, interactions with DNA/BSA and cytotoxicity against a series of cancer cells has been investigated.

Cited by 17 publications

References 64 publications

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

Development of Effective Therapeutic Molecule from Natural Sources against Coronavirus Protease

Synthesis, substitution kinetics, DNA/BSA binding and cytotoxicity of tridentate N^E^N (E = NH, O, S) pyrazolyl palladium(II) complexes

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