ParDOCK: An All Atom Energy Based Monte Carlo Docking Protocol for Protein-Ligand Complexes

Gupta, Aditya; Gandhimathi, A.; Sharma, Priyanka; Jayaram, B.

doi:10.2174/092986607781483831

Cited by 124 publications

(66 citation statements)

References 33 publications

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“…The docking results obtained using AutoDock were also confirmed using ParDOCK [49], which is an all atom energy based monte carlo docking protocol. Docking using ParDOCK requires a reference complex (target protein bound to a reference ligand) and a candidate molecule along with specific mention of the centre of mass of the cavity on which the ligand is to be docked.…”

Section: Methodsmentioning

confidence: 61%

Ashwagandha Derived Withanone Targets TPX2-Aurora A Complex: Computational and Experimental Evidence to its Anticancer Activity

et al. 2012

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Cancer is largely marked by genetic instability. Specific inhibition of individual proteins or signalling pathways that regulate genetic stability during cell division thus hold a great potential for cancer therapy. The Aurora A kinase is a Ser/Thr kinase that plays a critical role during mitosis and cytokinesis and is found upregulated in several cancer types. It is functionally regulated by its interactions with TPX2, a candidate oncogene. Aurora A inhibitors have been proposed as anticancer drugs that work by blocking its ATP binding site. This site is common to other kinases and hence these inhibitors lack specificity for Aurora A inhibition in particular, thus advocating the need of some alternative inhibition route. Previously, we identified TPX2 as a cellular target for withanone that selectively kill cancer cells. By computational approach, we found here that withanone binds to TPX2-Aurora A complex. In experiment, withanone treatment to cancer cells indeed resulted in dissociation of TPX2-Aurora A complex and disruption of mitotic spindle apparatus proposing this as a mechanism of the anticancer activity of withanone. From docking analysis, non-formation/disruption of the active TPX2-Aurora A association complex could be discerned. Our MD simulation results suggesting the thermodynamic and structural stability of TPX2-Aurora A in complex with withanone further substantiates the binding. We report a computational rationale of the ability of naturally occurring withanone to alter the kinase signalling pathway in an ATP-independent manner and experimental evidence in which withanone cause inactivation of the TPX2-Aurora A complex. The study demonstrated that TPX2-Aurora A complex is a target of withanone, a potential natural anticancer drug.

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Section: Methodsmentioning

confidence: 61%

Ashwagandha Derived Withanone Targets TPX2-Aurora A Complex: Computational and Experimental Evidence to its Anticancer Activity

et al. 2012

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“…A strong interaction with WT-ANG and the inhibitor was observed as expected in the native conformation possessing ribonucleolytic activity (see Figure S6). Similarly, docking between the inhibitor and K17I, S28N, P112L, V113I variants and L35P, K60E mutants were performed using AutoDock [29], [30] and ParDOCK [32]–[34] and the binding energies for each case were determined and presented (Table 3). It was observed that the binding energy in those cases where the dihedral angle of the His114 changes significantly was lower compared to the WT-ANG conformation.…”

Section: Resultsmentioning

confidence: 99%

“…The binding energies were also calculated using ParDOCK which is an all atom energy based Monte Carlo docking protocol [32]–[34]. Docking using ParDOCK requires a reference complex (target protein bound to a reference ligand) and a candidate molecule along with specific mention of the centre of mass of the cavity on which the ligand is to be docked.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

et al. 2012

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BackgroundMutations in the coding region of angiogenin (ANG) gene have been found in patients suffering from Amyotrophic Lateral Sclerosis (ALS). Neurodegeneration results from the loss of angiogenic ability of ANG (protein coded by ANG). In this work, we performed extensive molecular dynamics (MD) simulations of wild-type ANG and disease associated ANG variants to elucidate the mechanism behind the loss of ribonucleolytic activity and nuclear translocation activity, functions needed for angiogenesis.Methodology/Principal FindingsMD simulations were carried out to study the structural and dynamic differences in the catalytic site and nuclear localization signal residues between WT-ANG (Wild-type ANG) and six mutants. Variants K17I, S28N, P112L and V113I have confirmed association with ALS, while T195C and A238G single nucleotide polymorphisms (SNPs) encoding L35P and K60E mutants respectively, have not been associated with ALS. Our results show that loss of ribonucleolytic activity in K17I is caused by conformational switching of the catalytic residue His114 by 99°. The loss of nuclear translocation activity of S28N and P112L is caused by changes in the folding of the residues 31RRR33 that result in the reduction in solvent accessible surface area (SASA). Consequently, we predict that V113I will exhibit loss of angiogenic properties by loss of nuclear translocation activity and L35P by loss of both ribonucleolytic activity and nuclear translocation activity. No functional loss was inferred for K60E. The MD simulation results were supported by hydrogen bond interaction analyses and molecular docking studies.Conclusions/SignificanceConformational switching of catalytic residue His114 seems to be the mechanism causing loss of ribonucleolytic activity and reduction in SASA of nuclear localization signal residues 31RRR33 results in loss of nuclear translocation activity in ANG mutants. Therefore, we predict that L35P mutant, would exhibit loss of angiogenic functions, and hence would correlate with ALS while K60E would not show any loss.

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“…19 The docking method includes 4 steps: (a) identification of best possible grid/translational points in radius of 3 Å around the reference point (centre of mass); (b) generation of grid and preparation of energy grid in and around the active site of the DNA to pre-calculate the energy of each atom in the candidate ligand; (c) Monte Carlo docking and intensive configurational search of the ligand inside the active site; and (d) identification of the best docked structures on an energy criterion and prediction of the binding free energy of the complex, as reported. 20 The selected docked complexes were energy minimized in vacuum by using AMBER force field. 21 For vacuum minimization, 1000 steps of steepest descent and 1500 steps of conjugate gradient were carried out.…”

Section: Methodsmentioning

confidence: 99%

DNA minor groove binding of small molecules: Experimental and computational evidence

et al. 2010

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Eight indole derivatives were studied for their DNA binding ability using fluorescence quenching and molecular docking methods. These indole compounds have structural moieties similar as in few indole alkaloids. Experimental and theoretical studies have suggested that indole derivatives bind in the minor groove of DNA. Thermodynamic profiles of DNA complexes of indole derivatives were obtained from computational methods. The complexes were largely stabilized by H-bonding and van der Waal's forces with positive entropy values. Indole derivatives were found to possess some Purine (Pu) -Pyrimidine (Py) specificity with DNA sequences. The results obtained from experimental and computational methods showed good agreement with each other, supported by their correlation constant values.

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ParDOCK: An All Atom Energy Based Monte Carlo Docking Protocol for Protein-Ligand Complexes

Cited by 124 publications

References 33 publications

Ashwagandha Derived Withanone Targets TPX2-Aurora A Complex: Computational and Experimental Evidence to its Anticancer Activity

Ashwagandha Derived Withanone Targets TPX2-Aurora A Complex: Computational and Experimental Evidence to its Anticancer Activity

Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

DNA minor groove binding of small molecules: Experimental and computational evidence

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