The molecular docking of 1,4-naphthoquinone derivatives as inhibitors of Polo-like kinase 1 using Molegro Virtual Docker

Kusumaningrum, Susi; Budianto, Emil; Kosela, Soleh; Sumaryono, Wahono; Juniarti, Fifit

doi:10.7324/japs.2014.4119

Cited by 19 publications

(10 citation statements)

References 20 publications

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“…The co-crystallized ligand, water molecules, and other co-factors were removed from the PDB structure using UCSF Chimera software. The structure of the ligand (methyl(2 E )-4-[(1-cyclopentyl-5-methoxy-2-methylindol-3-yl)formamido]but-2-enoate) [9] was drawn in mol2 format using MarvinSketch 6.2.1, 2014, ChemAxon (); hybridization state and proper angles were assessed using Molegro Molecular Viewer (MMV) [14].…”

Section: Methodsmentioning

confidence: 99%

Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling

et al. 2019

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The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery.

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Section: Methodsmentioning

confidence: 99%

Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling

et al. 2019

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“…The X-ray crystal structure of the c-ring rotor (F o portion) of mycobacterial ATP synthase was obtained from RSCB Protein Data Bank with code 4V1F, 17 which was already complexed with BDQ (ID:5388906). This complex was then prepared for simulation using UCSF Chimera 29 and the Molecular Molegro Viewer (MMV), 30 a technical procedure that basically involves the removal of cocrystallized molecules not relevant to the study such as crystal waters. The structure comprised of three chains A, B, and C with BDQ bound to all three, however only the central region of the three BDQ molecules within the crystal structure was visible whereas parts of the other two molecules were partially visible.…”

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confidence: 99%

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Salifu

Agoni

Dokurugu

2019

J of Cellular Biochemistry

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Therapeutic targeting of the adenosine triphosphate (ATP) machinery of Mycobacterium tuberculosis (Mtb) has recently presented a potent and alternative measure to halt the pathogenesis of tuberculosis. This has been potentiated by the development of bedaquiline (BDQ), a novel small molecule inhibitor that selectively inhibits mycobacterial F1Fo‐ATP synthase by targeting its rotor c‐ring, resulting in the disruption of ATP synthesis and consequential cell death. Although the structural resolution of the mycobacterial C9 ring in co`mplex with BDQ provided the first‐hand detail of BDQ interaction at the c‐ring region of the ATP synthase, there still remains a need to obtain essential and dynamic insights into the mechanistic activity of this drug molecule towards crucial survival machinery of Mtb. As such, for the first time, we report an atomistic model to describe the structural dynamics that explicate the experimentally reported antagonistic features of BDQ in halting ion shuttling by the mycobacterial c‐ring, using molecular dynamics simulation and the Molecular Mechanics/Poisson‐Boltzmann Surface Area methods. Results showed that BDQ exhibited a considerably high ΔG while it specifically maintained high‐affinity interactions with Glu65B and Asp32B, blocking their crucial roles in proton binding and shuttling, which is required for ATP synthesis. Moreover, the bulky nature of BDQ induced a rigid and compact conformation of the rotor c‐ring, which impedes the essential rotatory motion that drives ion exchange and shuttling. In addition, the binding affinity of a BDQ molecule was considerably increased by the complementary binding of another BDQ molecule, which indicates that an increase in BDQ molecule enhances inhibitory potency against Mtb ATP synthase. Taken together, findings provide atomistic perspectives into the inhibitory mechanisms of BDQ coupled with insights that could enhance the structure‐based design of novel ATP synthase inhibitors towards the treatment of tuberculosis.

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“…The protocols utilized to perform docking consist of two major components: a search algorithm and a scoring function ( Damm-Ganamet et al, 2013 ). The search algorithm defines the three-dimensional shapes of the ligand and the protein as they are bound to each other ( Kusumaningrum et al, 2014 ). The scoring function of the docking process specifies a numeric score to a specific three-dimensional protein-ligand structure that indicates the affinity between the two molecules.…”

Section: Manuscript Formattingmentioning

confidence: 99%

Cytotoxicity of Amphotericin B and AmBisome: In Silico and In Vivo Evaluation Employing the Chick Embryo Model

et al. 2022

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Leishmaniasis has been identified as a significant disease in tropical and subtropical regions of the world, with Iran being one of the disease-endemic areas. Various treatments have been applied for this disease, and amphotericin B (Amp B) is the second line of treatment. Side effects of this drug have been reported in various organs. The present study investigated the effects of different types of Amp B on fetal organs using in silico and in vivo assays (chicken embryos). In vivo analysis was done by checking pathological changes, angiogenesis, and apoptosis alterations on eggs treated by Amp B and AmBisome. In silico approach was employed to predict the affinity of Amp B and AmBisome to the vascular endothelial growth factor A (VEGF-A), its receptor (KDR1), apoptotic-regulator proteins (Bcl-2-associated X protein (Bax), B-cell lymphoma (Bcl-2), and Caspase-8. The ADME-toxicity prediction reveals that AmBisome possesses a superior pharmacological effect to Amp B. The best result of all the dockings in the Molegro Virtual Docker (MVD) was obtained between Bax, Bcl-2, Caspase-8, KDR1, and VEGF-A targets. Due to the lower Egap (HOMO–LUMO) of AmBisome, the chemical reactivity of AmBisome was higher than that of Amp B. In vivo analysis showed that embryos that received Amp B exhibited less vascular density than AmBisome. Amp B alone significantly increased the expression of apoptosis and decreased angiogenesis genes compared to AmBisome. The histopathology analysis of the treated embryos showed a reduction in the blood vessel collapse and an increase in degenerative and apoptotic–necrotic changes in the embryonic tissues. Overall, the results suggest the potential benefits of AmBisome over Amp B, which might be a better treatment strategy to treat leishmaniasis during pregnancy.

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The molecular docking of 1,4-naphthoquinone derivatives as inhibitors of Polo-like kinase 1 using Molegro Virtual Docker

Cited by 19 publications

References 20 publications

Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling

Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Cytotoxicity of Amphotericin B and AmBisome: In Silico and In Vivo Evaluation Employing the Chick Embryo Model

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