Detailed analysis of grid‐based molecular docking: A case study of CDOCKER—A CHARMm‐based MD docking algorithm

Wu, Guosheng; Robertson, Daniel H.; Brooks, Charles L.; Vieth, Michał

doi:10.1002/jcc.10306

Cited by 1,364 publications

(998 citation statements)

References 36 publications

Supporting

Mentioning

988

Contrasting

Unclassified

Order By: Relevance

“…Using a CHARMmbased molecular dynamics simulated-annealing program CDOCKER (29), TFD-etomidate (volume, 230 Å 3 ) was docked into the ion channel, the ␦ subunit helix bundle, and the ␥ -␣ subunit interface. Twenty randomly distributed replicas of TFD-etomidate were seeded in the center of spheres (r ϭ 15 Å) positioned within the ion channel extending from M2-2 to M2-20 or within the ␦ subunit helix bundle extending from the level of M2-13 to the M2-M3 loop.…”

Section: Isolation Of [ 3 H]tfd-etomidate-labeled Nachr Subunitmentioning

confidence: 99%

Multiple Transmembrane Binding Sites for p-Trifluoromethyldiazirinyl-etomidate, a Photoreactive Torpedo Nicotinic Acetylcholine Receptor Allosteric Inhibitor

Hamouda

Stewart

Husain

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The excitatory nicotinic acetylcholine receptors (nAChRs) 2 and serotonin 5-HT 3 receptors and the inhibitory ␥-aminobutyric acid type A receptors (GABA A Rs) and glycine receptors are members of the Cys-loop superfamily of neurotransmittergated ion channels (1-3). Models of the three-dimensional structures of these receptors can be derived from the cryoelectron microscopy structure of the Torpedo nAChR in the absence of agonist (4) and from the high resolution crystal structures of distantly related prokaryotic channels (5, 6) and the soluble molluscan acetylcholine-binding proteins (for review, see Ref. 7).The Torpedo nAChR is composed of four homologous subunits (␣ 2 ␤␥␦) that assemble around an axis perpendicular to the membrane, forming a cation-conducting channel. Each subunit is made up of three structural domains; that is, an N-terminal extracellular domain, with the two ACh binding sites at the interfaces between the ␣-␥ and ␣-␦ subunits (8), a transmembrane domain made up of a loose bundle of four transmembrane helices (M1-M4), and a cytoplasmic domain between the M3 and M4 helices (M3-M4 loop). Amino acids on one face of each M2 helix form the lining of the ion channel, and the M1, M3, and M4 helices form an outer ring that is in contact with membrane lipids (4, 9).Muscle or neuronal nAChRs are targets for drugs potentially useful for treatment of myasthenia gravis and CNS disorders, including nicotine addiction, Alzheimer disease, and schizophrenia (10). In an attempt to develop drugs with strong selectivity for subtypes of muscle or neuronal nAChRs, screens of natural products and synthetic libraries have identified many drugs that act either as positive or negative allosteric modulators (11,12). However, there is limited information about the diversity of allosteric modulator binding sites or whether positive and negative modulators can bind to the same site, as occurs, for example, at the benzodiazepine site in the GABA A R (13).In addition to binding sites for non-competitive antagonists within the ion channel (14), the transmembrane domain con-

show abstract

Section: Isolation Of [ 3 H]tfd-etomidate-labeled Nachr Subunitmentioning

confidence: 99%

Multiple Transmembrane Binding Sites for p-Trifluoromethyldiazirinyl-etomidate, a Photoreactive Torpedo Nicotinic Acetylcholine Receptor Allosteric Inhibitor

Hamouda

Stewart

Husain

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The low-energy ligand conformations were docked into the active site of CTX-M-9, and the structure was further refined using the ChiRotor algorithm. A final simulated annealing and energy minimization of each ligand pose was performed using the program CDOCKER (61).…”

Section: Esi-ms Electrospray Ionization Mass Spectrometry (Esi-ms) Omentioning

confidence: 99%

Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems

Bethel

Taracila

Shyr

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Currently, CTX-M ␤-lactamases are among the most prevalent and most heterogeneous extended-spectrum ␤-lactamases (ESBLs). In general, CTX-M enzymes are susceptible to inhibition by ␤-lactamase inhibitors. However, it is unknown if the pathway to inhibition by ␤-lactamase inhibitors for CTX-M ESBLs is similar to TEM and SHV ␤-lactamases and why bacteria possessing only CTX-M ESBLs are so susceptible to carbapenems. Here, we have performed a kinetic analysis and timed electrospray ionization mass spectrometry (ESI-MS) studies to reveal the intermediates of inhibition of CTX-M-9, an ESBL representative of this family of enzymes. CTX-M-9 ␤-lactamase was inactivated by sulbactam, tazobactam, clavulanate, meropenem, doripenem, ertapenem, and a 6-methylidene penem, penem 1. CTX-M enzymes are becoming one of the most prevalent extended-spectrum ␤-lactamases (ESBLs) (3,8,9,(30)(31)(32) in the world. The widespread dissemination of CTX-M ␤-lactamases, especially Escherichia coli ST131 possessing CTX-M-15, has had a significant impact on the treatment of hospital-and community-acquired infections caused by E. coli and other enteric bacilli (6, 7, 13, 23, 36, 41, 44-49, 55, 59).As class A family ␤-lactamases, CTX-Ms are the most genetically heterogeneous (5 major divisions, CTX-M-1, -2, -8, -25, and -9-like groups) (1, 24, 35, 44-46, 58, 60). Most CTX-M enzymes expressed in E. coli provide a high level of resistance to the oxyimino-cephalosporins, cefotaxime and ceftriaxone, and variable levels of resistance to cefepime and cefpirome (3,43). Depending on the type of CTX-M expressed by the isolates, the MICs of ceftazidime are also increased (43). In addition, the MICs of combinations of clavulanate with amoxicillin or ticarcillin vary, and in some cases, low-level resistance has been observed (3).As a consequence of their clinical importance, the reaction mechanism of CTX-M ESBLs has been the subject of intense study (10-12, 14, 16, 42). However, the molecular properties and characteristics of CTX-M that determine the level of susceptibility and resistance to ␤-lactam-␤-lactamase inhibitor combinations and carbapenems are still unknown. Of the currently available inhibitors, tazobactam is the most active (50% inhibitory concentrations [IC 50 s] are 2 to 10 nM for tazobactam and 9 to 90 nM for clavulanate), and sulbactam is the least active (IC 50 s are 0.1 to 4.5 M) (3).In order to develop more effective and broader-spectrum ␤-lactamase inhibitors (18), detailed kinetic and biochemical measurements are needed to reveal the important intermediates in the inactivation of the CTX-M family. In TEM-1 and SHV-1, Arg244 is important in the mechanism of inactivation of carbapenems (imipenem and meropenem), clavulanic acid, sulbactam, and tazobactam (27,28,51,53,63). CTX-M-9 does not contain Arg244, and mutagenesis of a potential corresponding position, Arg276, does not firmly establish this amino acid as an "Arg244 equivalent" (42). Given the differences among class A enzymes, we wondered what the intermediates of inactivation by ...

show abstract

“…Hydrogen atoms were added to correct the chemistry of protein and energy minimization was performed to avail a stable conformation by employing CHARMm force field [18]. The energy minimized structure was used as the template for molecular docking.…”

Section: Methodsmentioning

confidence: 99%

6-Gingerol is the most Potent Anticancerous Compound in Ginger (Zingiber officinale Rosc.)

Kumara¹,

Mr²,

Pa³

et al. 2017

J Dev Drugs

View full text Add to dashboard Cite

Cancer is one of the most deadly diseases in the world, which is caused due to uncontrolled growth of cells or malfunction of genes that control normal cell growth and division. Because of high death rate associated with cancer and because of serious side effects of chemotherapy and radiation therapy, many cancer patients seek alternative complementary methods of treatment. Ginger (Zingiber officinale Rosc.) is an important spice crop with immense medicinal properties and health beneficial effects. All the ginger ligands showed good interaction with the selected targets but based on ADME/Toxicity analysis 6-gingerol was superior with respect to absorption, solubility, and less neurotoxic effect as compared to other ginger ligands. 6-gingerol was also found cytotoxic to all the three cancer cells lines were studied. The cytotoxicity increased with increase in concentration of 6-gingerol. The IC50 values recorded for different cancer cell lines, 24 h. after treatment (100 μM for HCT15, 102 μM for L929 and 102 μM for Raw 264.7) showed uniform cytotoxicity in the three cell lines studied. The study highlights the potential of 6-gingerol for drug development against cancer.

show abstract

Detailed analysis of grid‐based molecular docking: A case study of CDOCKER—A CHARMm‐based MD docking algorithm

Cited by 1,364 publications

References 36 publications

Multiple Transmembrane Binding Sites for p-Trifluoromethyldiazirinyl-etomidate, a Photoreactive Torpedo Nicotinic Acetylcholine Receptor Allosteric Inhibitor

Multiple Transmembrane Binding Sites for p-Trifluoromethyldiazirinyl-etomidate, a Photoreactive Torpedo Nicotinic Acetylcholine Receptor Allosteric Inhibitor

Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems

6-Gingerol is the most Potent Anticancerous Compound in Ginger (Zingiber officinale Rosc.)

Contact Info

Product

Resources

About