Modelling of Factor Xa-inhibitor complexes: a computational flexible docking approach

Rao, M. Srinivasa; Olson, Arthur J.

doi:10.1002/(sici)1097-0134(19990201)34:2<173::aid-prot3>3.0.co;2-f

Cited by 55 publications

(37 citation statements)

References 26 publications

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“…Those values not only reproduce the experimental ranking of binding efficiencies but also are in the same range, the measured K i being 2.5⅐10 Ϫ5 Ϯ 0.5 M for acetylcholine, 0.55⅐10 Ϫ6 Ϯ 0.02 M for nicotine (42), and 1.9⅐10 Ϫ7 Ϯ 0.1 M for epibatidine (43). The binding free energy computed by AUTODOCK has been shown to reproduce correctly the experimental values (44). However, because of uncertainty on the comparative modeling process, absolute values have to be considered with caution at this stage.…”

Section: Model Of Chick ␣7mentioning

confidence: 99%

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca ²⁺ -binding sites

Novère

Grütter

Changeux

2002

Proc. Natl. Acad. Sci. U.S.A.

264

202

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We constructed a three-dimensional model of the amino-terminal extracellular domain of three major types of nicotinic acetylcholine receptor, (␣7)5, (␣4)2(␤2)3, and (␣1)2␤1␥␦, on the basis of the recent x-ray structure determination of the molluscan acetylcholine-binding protein. Comparative analysis of the three models reveals that the agonist-binding pocket is much more conserved than the overall structure. Differences exist, however, in the side chains of several residues. In particular, a phenylalanine residue, present in ␤2 but not in ␣7, is proposed to contribute to the high affinity for agonists in receptors containing the ␤2 subunit. The semiautomatic docking of agonists in the ligand-binding pocket of (␣7)5 led to positions consistent with labeling and mutagenesis experiments. Accordingly, the quaternary ammonium head group of nicotine makes a -cation interaction with W148 (␣7 numbering), whereas the pyridine ring is close to both the cysteine pair 189 -190 and the complementary component of the binding site. The intrinsic affinities inferred from docking give a rank order epibatidine > nicotine > acetylcholine, in agreement with experimental values. Finally, our models offer a structural basis for potentiation by external Ca 2؉ .

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Section: Model Of Chick ␣7mentioning

confidence: 99%

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca ²⁺ -binding sites

Novère

Grütter

Changeux

2002

Proc. Natl. Acad. Sci. U.S.A.

264

202

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“…The AutoDock suite of programs, which was used for the docking calculation, employs an automated docking approach, allowing ligand flexibility as described to a full extent elsewhere (22). AutoDock has been compared with various other docking programs and has been found to be able to locate docking modes that are consistent with X-ray crystal structure (23)(24)(25)(26).…”

Section: Molecule Building and Nucleophilic Susceptibility Analysismentioning

confidence: 94%

Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs

Kanwar

Mohammad²,

Yang³

et al. 2010

Int J Mol Med

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Abstract. (-)-Epigallocatechin gallate [(-)-EGCG] has beenimplicated in cancer chemoprevention and has been shown as an inhibitor of tumor proteasomal chymotrypsin-like activity in vitro and in vivo. However, EGCG is subjected to rapid biotransforming modifications such as methylation by catechol-O-methyltransferase (COMT) that limits its action. We recently reported that structure 7, an EGCG analog which should be resistant to COMT-mediated methylation and inactivation in cells, was able to inhibit the activity of purified 20S proteasome and cellular 26S proteasome. However, the involved molecular mechanism is unknown. Herein, we applied computational solution to understand the possible interaction between EGCG analogs including structure 7 and the proteasome ß5 subunit which is responsible for the chymotrypsin-like activity. We report that the ester carbonyls at C2 and C3 carbon atoms may be the active sites for nucleophilic attack in structure 7 and 5. Equally spaced carbon atoms in COMT-resistant structure 7 give more stable conformation and lower docked free energy than other EGCG analogs. The absence of a second gallate group in structure 16 and 21 significantly decreases the ability to inhibit the proteasome.

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“…The docking algorithm makes use of force field equations and parameters to calculate the binding energy between ligand and enzyme [19][20][21][22][23][24][25]. The binding free energy is the total of van der Waals interactions, H-bond interactions, electrostatic interactions and the internal static energy of the ligand as shown in Equation 1 [26][27][28][29][30][31][32][33].…”

Section: Dockingmentioning

confidence: 99%

Inhibition Studies of Naturally Occurring Terpene based Compounds with Cyclin-Dependent Kinase 2 Enzyme

Ganatra¹

2012

JCSB

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The knowledge of the molecular basis of carcinogenesis has helped to discover new, less toxic chemotherapy agents. At present, considerable attention has been focused on identifying the molecular level interactions of naturally occurring Terpene based substances, capable of inhibiting target enzymes. CDKs enzymes are known as cell regulators in eukaryotic cell cycle. In finding new anti-cancer agents, CDKs are used as target enzymes, particular among them are CDK2 enzymes.Computer based Chem-office and Autodock molecular modeling tools used to understand the ways with which Terpene based natural products interacts with Cyclin-dependent kinase 2 (CDK2). Using in-silico techniques, the binding energy between ligands and receptor enzyme are calculated in the form of ∆G in Kcal.mol -1 . The reported binding energies for series of molecules are ranging from -7.96 to -16.62 Kcal.mol -1 . The negative docking energies and a few hydrogen bonds between ligand and receptor enzyme support the affinity of Terpene based compounds with selected enzyme. Number of hydroxyl groups present in ligand enhances the interaction strength and stability of complex. The finding confirms the affinity of Terpene based natural products as CDK2 inhibitor. Inhibition Studies of Naturally Occurring Terpene based Compounds with Cyclin-Dependent Kinase 2 EnzymeSunil H Ganatra* and Amita S Suchak Department of Chemistry, Institute of Science, Civil Lines, India Citation: Ganatra SH, Suchak AS (2012) Inhibition Studies of Naturally Occurring Terpene based Compounds with Cyclin-Dependent Kinase 2 Enzyme. J Comput Sci Syst Biol 5: 068-073.

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Modelling of Factor Xa-inhibitor complexes: a computational flexible docking approach

Cited by 55 publications

References 26 publications

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca ²⁺ -binding sites

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca ²⁺ -binding sites

Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs

Inhibition Studies of Naturally Occurring Terpene based Compounds with Cyclin-Dependent Kinase 2 Enzyme

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Modelling of Factor Xa-inhibitor complexes: a computational flexible docking approach

Cited by 55 publications

References 26 publications

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca 2+ -binding sites

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca 2+ -binding sites

Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs

Inhibition Studies of Naturally Occurring Terpene based Compounds with Cyclin-Dependent Kinase 2 Enzyme

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Product

Resources

About

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca ²⁺ -binding sites

Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca ²⁺ -binding sites