Validation of the general purpose tripos 5.2 force field

Clark, Matthew; Cramer, Richard D.; Opdenbosch, N. Van

doi:10.1002/jcc.540100804

Cited by 2,750 publications

(1,725 citation statements)

References 19 publications

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“…(1) The binding free energy evaluated by a three-parameter LIECE model (see next section), (2) the CHARMm [16] protein-compound electrostatic interaction energy with ǫ(r) = 4r and cutoff at 14Å, (3) the CHARMm protein-compound van der Waals interaction energy (cutoff at 14Å) divided by the molecular weight of the compound (van der Waals efficiency), (4) the TAFF [17] protein-compound interaction energy.…”

Section: Consensus Scoringmentioning

confidence: 99%

“…The binding free energy approximated by the linear interaction energy with contin-uum electrostatics (LIECE) method [15], the CHARMm [16] electrostatic interaction energy, the CHARMm van der Waals efficiency, and the TAFF [17] interaction energy. Only 59 molecules were tested in an enzymatic assay, and 13 of them show inhibitory activity (IC 50 < 100 µM; IC 50 = concentration of inhibitor at which 50% of the maximum initial rate is observed).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

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Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high‐throughput fragment‐based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium‐ and high‐throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

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Section: Consensus Scoringmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

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“…All the hydrogen atoms were added, and the structures were subsequently submitted to full energy minimization using the Conjugate Gradient energy minimization algorithm with gradient 0.01 kcal mol −1 Å −1 . The Tripos force field 54 was used for the minimization procedure with nonbonded interactions cutoff of 8.0 Å, using a distance dependent dielectric function with dielectric constant of 1.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Molecular Modeling on Pyrimidine-Urea Inhibitors of TNF-α Production: An Integrated Approach Using a Combination of Molecular Docking, Classification Techniques, and 3D-QSAR CoMSIA

Mouchlis

Melagraki

Mavromoustakos

et al. 2012

J. Chem. Inf. Model.

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Molecular docking, classification techniques, and 3D-QSAR CoMSIA were combined in a multistep framework with the ultimate goal of identifying potent pyrimidine-urea inhibitors of TNF-α production. Using the crystal structure of p38α, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment for the generation of the CoMSIA fields. "Active" and "inactive" compounds were used to build a Random Tree classification model using the docking score and the CoMSIA fields as input parameters. Domain of applicability indicated the compounds for which activity estimations can be accepted with confidence. For the active compounds, a 3D-QSAR CoMSIA model was subsequently built to accurately estimate the IC 50 values. This novel multistep framework gives insight into the structural characteristics that affect the binding and the inhibitory activity of these analogues on p38α MAP kinase, and it can be extended to other classes of small-molecule inhibitors. In addition, the simplicity of the proposed approach provides expansion to its applicability such as in virtual screening procedures.

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“…Using the structure of RNase Ba from the crystal complex of RNase Ba (M-chain in asymmetric unit) with d(CGAC) as template [7], the structure of RNase Bpo was modelled with the aid of interactive computer graphics [17]. Then, the structure of RNase Bpo with d(CGAC) was obtained from overlay of the RNase Ba-d(CGAC) complex structure with the predicted RNase Bpo structure.…”

Section: Methodsmentioning

confidence: 99%

“…Then, the structure of RNase Bpo with d(CGAC) was obtained from overlay of the RNase Ba-d(CGAC) complex structure with the predicted RNase Bpo structure. The structure of the RNase Bpo-d(CGAC) complex was subjected to energy minimization calculations, employing the TRIPOS force field [17]. The pH of the system was set to 7.0; all residues of Asp, Glu and the C-terminus were taken as negatively charged, all residues of Arg, Lys, His and the N-terminus being considered to be positively charged.…”

Section: Methodsmentioning

confidence: 99%

Structural characterization of extracellular ribonuclease of Bacillus polymyxa: amino acid sequence determination and spatial structure prediction

et al. 1996

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The primary structure of extracellular Bacillus polymyxa ribonuclease (RNase Bpo) was established by mass spectroscopy analysis and automatic Edman degradation of the individual peptides obtained from protein digestion with Ginspecific protease V8. RNase Bpo consists of 111 amino acid residues, with a relative molecular weight of 12 607. RNase Bpo is a close structural homolog of RNases of B. arayloliquefaciens (RNase Ba) and B. intermedius (RNase Bi), the similarity of their primary structures being 68%. Molecular modelling of the structure of the complex of RNase Bpo with substrate analog d(CGAC) was performed and a spatial model based on the known crystal structure of RNase Ba complex with the corresponding nucleotide was constructed using the methods of interactive computer graphics and energy minimization. The differences in the primary and tertiary structures of the enzymes were analyzed in order to understand the substrate specificity of Bacillus RNases.Aey words." Ribonuclease; Primary structure; Molecular modeling; Protein-nucleic acid interaction; B,~cillus polymyxa 1, IntroductionExtracellular Bacillus RNases belong to the family of structurally related and mutually homologous low molecular ~eight microbial cyclizing RNases [1,2]. The best-studied representatives of Bacillus RNases are the RNases of B. amyloli~mefaciens (RNase Ba) and B. intermedius (RNase Bi). The a~nino acid sequences of RNases Ba and Bi were found to be different in 18 sites [3][4][5]. The spatial structures of the enzymes c,,mplexed with various specific substrate analogs were solved a high resolution [6][7][8], and the substrate specificity and mechanism of catalysis were studied in detail [9][10][11][12][13].Some years ago, three related RNases of B. thuringiensis (RNase Bth), B. coagulans (RNase Bco) and B. circulans (RNase Bci) were obtained in a homogeneous state and their physical-chemical, functional and structural characteristics ~re studied [5,14,15]. RNases Bth and Bco were shown to *~ ;orresponding author.Aobreviations: RNases Bpo, Ba, Bi, Bth, Bco and Bci, ribonucleases of Bacillus polymyxa, B. amyloliquefaciens, B. intermedius, B. thuringiensi,, B. coagulans and B. circulans, respectively (EC 3.1.27.1); V8 protease, endoprotease from Staphylococcus aureus strain V8 (EC 3A.21.19); Barstar, intracellular protein inhibitor of RNase Ba; dl CGAC), 2'-deoxycytosylyl-(3',5')-2'-deoxyguanylyl-(3',5')-2'-deoxyadenylyl-(3',5')-2'-deoxycytidine; rms, root-mean-square. have the same primary structure which is identical to that of RNase Bi in all but one residue, while differences in the amino acid sequences of RNases Bci and Ba were found in three positions.Recently, we have isolated a novel extracellular RNase of B. polymyxa (RNase Bpo) and have determined its partial N-and C-terminal amino acid sequences [16]. It is interesting that the substrate specificity of RNase Bpo is markedly different from that of the above-mentioned Bacillus RNases and the identity of the N-terminal amino acid sequences (32 residues) of all th...

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Validation of the general purpose tripos 5.2 force field

Cited by 2,750 publications

References 19 publications

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Molecular Modeling on Pyrimidine-Urea Inhibitors of TNF-α Production: An Integrated Approach Using a Combination of Molecular Docking, Classification Techniques, and 3D-QSAR CoMSIA

Structural characterization of extracellular ribonuclease of Bacillus polymyxa: amino acid sequence determination and spatial structure prediction

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