Computer-Aided Design of Thrombin Inhibitors

Caflisch, Amedeo; Wälchli, Rudolf; Ehrhardt, Claus

doi:10.1152/physiologyonline.1998.13.4.182

Cited by 12 publications

(16 citation statements)

References 14 publications

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“…Random sampling is not susceptible to the ‘curse of dimensionality’ that is common to regular grid spacing methods allowing for more efficient estimation of the NRMSD landscape in Figure 7(C,D) , and random points fill in the parameter space more evenly than regular grid spacing that forces evaluations of the model within the same parameter hyperplane ( Caflisch et al, 1998 ). Figure 7C,D demonstrates the dense coverage and sampling to estimate the NRMSD values and dense coverage in regions with acceptable NRMSD values.…”

Section: Methodsmentioning

confidence: 99%

Systems biology derived source-sink mechanism of BMP gradient formation

Zinski

Wang

et al. 2017

eLife

125

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A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral embryonic axis of vertebrates and invertebrates. The prevailing view in vertebrates for BMP gradient formation is through a counter-gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels. To delineate the mechanism in zebrafish, we precisely quantified the BMP activity gradient in wild-type and mutant embryos and combined these data with a mathematical model-based computational screen to test hypotheses for gradient formation. Our analysis ruled out a BMP shuttling mechanism and a bmp transcriptionally-informed gradient mechanism. Surprisingly, rather than supporting a counter-gradient mechanism, our analyses support a fourth model, a source-sink mechanism, which relies on a restricted BMP antagonist distribution acting as a sink that drives BMP flux dorsally and gradient formation. We measured Bmp2 diffusion and found that it supports the source-sink model, suggesting a new mechanism to shape BMP gradients during development.

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Section: Methodsmentioning

confidence: 99%

Systems biology derived source-sink mechanism of BMP gradient formation

Zinski

Wang

et al. 2017

eLife

125

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“…So appropriate structural analysis and accurate estimation of binding free energy for ligand-receptor complexes are the most important two steps of structure-based ligand design approach. [3][4][5][6][7][8] The binding free-energy calculation can be time consuming, because it requires an accurate determination of the interactions and a reliable treatment of solvent effects. Finding methods for evaluation of the ligand-binding affinity that are fast enough to treat thousands of candidate ligands in a reasonable time is a major challenge in drug design.…”

Section: Introductionmentioning

confidence: 99%

An estimation method of binding free energy in terms of ABEEMσπ/MM and continuum electrostatics fused into LIE method

2010

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A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. The linear interaction energy method is combined with atom-bond electronegativity equalization method at σπ level Force field (fused into molecular mechanics) and generalized Born continuum model calculation of electrostatic solvation for the estimation of the absolute free energy of binding. The parameters of this method are calibrated by using a training set of 24 HIV-1 protease-inhibitor complexes (PDB entry 1AAQ). A correlation coefficient of 0.93 was obtained with a root mean square deviation of 0.70 kcal mol(-1) . This approach is further tested on seven inhibitor and protease complexes, and it provides small root mean square deviation between the calculated binding free energy and experimental binding free energy without reparametrization. By comparing the radii of gyration and the hydrogen bond distances between ligand and protein of three training model molecules, the consistent comparison result of binding free energy is obtained. It proves that this method of calculating the binding free energy with appropriate structural analysis can be applied to quickly assess new inhibitors of HIV-1 proteases. To test whether the parameters of this method can apply to other drug targets, we have validated this method for the drug target cyclooxygenase-2.

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“…Computer‐aided structure‐based ligand design methods are useful tools for de novo design and lead modification 1–3. The combinatorial strategy we have chosen for structure‐based ligand design consists of three parts: the docking of small molecular fragments, the connection of the docked fragments by combinatorial principles to generate candidate ligands, and the estimation of relative binding affinities 4.…”

Section: Introductionmentioning

confidence: 99%

Exhaustive docking of molecular fragments with electrostatic solvation

et al. 1999

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A new method is presented for docking molecular fragments to a rigid protein with evaluation of the binding energy. Polar fragments are docked with at least one hydrogen bond with the protein while apolar fragments are positioned in the hydrophobic pockets. The electrostatic contribution to the binding energy, which consists of screened intermolecular energy and protein and fragment desolvation terms, is evaluated efficiently by a numerical approach based on the continuum dielectric approximation. The latter is also used to predetermine the hydrophobic pockets of the protein by rolling a low dielectric sphere over the protein surface and calculating the electrostatic desolvation of the protein and van der Waals interaction energy. The method was implemented in the program SEED (solvation energy for exhaustive docking). The SEED continuum electrostatic approach has been successfully validated by a comparison with finite difference solutions of the Poisson equation for more than 2,500 complexes of small molecules with thrombin and the monomer of HIV-1 aspartic proteinase. The fragments docked by SEED in the active site of thrombin reproduce the structural features of the interaction patterns between known inhibitors and thrombin. Moreover, the combinatorial connection of these fragments yields a number of compounds that are very similar to potent inhibitors of thrombin. Proteins 1999;37:88-105.

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Computer-Aided Design of Thrombin Inhibitors

Cited by 12 publications

References 14 publications

Systems biology derived source-sink mechanism of BMP gradient formation

Systems biology derived source-sink mechanism of BMP gradient formation

An estimation method of binding free energy in terms of ABEEMσπ/MM and continuum electrostatics fused into LIE method

Exhaustive docking of molecular fragments with electrostatic solvation

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