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Results for “Molecular Docking Simulation”

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PubMed1994

MONTY: a Monte Carlo approach to protein-DNA recognition.

A Monte Carlo method is described for automated docking of proteins on DNA. The simulation program MONTY keeps the entire DNA and the protein backbone and core fixed while protein surface side-chains are allowed to rotate freely. The entire protein is rotated and translated by small random steps in order to find the best fit with the DNA. New configurations are accepted on basis of their Boltzmann probability. Protein-DNA interaction is represented by square well potentials for hydrogen bond and van der Waals interactions. The structure with the largest interaction energy encountered during the simulation is saved. The method is tested on complexes of the 434 Cro protein and its operator DNA where the protein is shifted up or down one or two base-pairs and is subsequently allowed to find back its native binding site. This protocol is performed for shifted complexes derived from the crystal structure, shifted complexes where the crystal structure DNA is replaced by standard B-DNA and shifted complexes where in addition the protein is replaced by protein from the uncomplexed crystal structure. In all three cases the six lowest energy structures correspond to complexes close to the native complex. The quality of sequence specific recognition diminishes, however, when the molecular surface complementarity between protein and DNA decreases.

Base Composition↗

PubMed2002

Molecular dynamics simulation of GM1 in phospholipid bilayer.

We report molecular dynamics simulation of fully hydrated lipid bilayer of dimyristoyl phosphatidyl choline (DMPC) at room temperature with ganglioside GM1 attached to it in the upper layer under periodic boundary conditions. The simulation results indicate that the presence of a single GM1 molecule has local effects on the bilayer. Three sugar residues (GalNAc-Gal-Glc) of the pentasaccharide head group of GM1 remain on the lipid surface where as the NeuNAc residue extends out in the aqueous layer. The radial distribution functions suggest ordering of water molecules near the glycerol and carboxyl group of the sialic acid in the upper layer. One of the ceramide chains of GM1, the sphingosine chain, folds up and is stacked under the sugar residues lying on the surface. The other ceramide chain is inserted into the lipid bilayer. The arrangement of the polar head group as well as the acyl chains of the lipids which are immediate neighbours of the GM1 are modified compared to the non-neighbour ones and others at the lower layer. The time average conformation of GM1-pentasaccharide is stabilized by a number of inter residue hydrogen bonds that were observed experimentally. The trajectory average conformation of GM1-pentasaccharide was docked on to the cholera toxin molecule and the minimized complex reveals alternative binding modes between the toxin and the GM1-pentasaccharide moiety. The results of these simulation studies might help to understand the structure and nature of the effects of GM1 on the membrane at atomic resolution.

Cholera Toxin↗

PubMed2005

Optimal docking area: a new method for predicting protein-protein interaction sites.

Understanding energetics and mechanism of protein-protein association remains one of the biggest theoretical problems in structural biology. It is assumed that desolvation must play an essential role during the association process, and indeed protein-protein interfaces in obligate complexes have been found to be highly hydrophobic. However, the identification of protein interaction sites from surface analysis of proteins involved in non-obligate protein-protein complexes is more challenging. Here we present Optimal Docking Area (ODA), a new fast and accurate method of analyzing a protein surface in search of areas with favorable energy change when buried upon protein-protein association. The method identifies continuous surface patches with optimal docking desolvation energy based on atomic solvation parameters adjusted for protein-protein docking. The procedure has been validated on the unbound structures of a total of 66 non-homologous proteins involved in non-obligate protein-protein hetero-complexes of known structure. Optimal docking areas with significant low-docking surface energy were found in around half of the proteins. The 'ODA hot spots' detected in X-ray unbound structures were correctly located in the known protein-protein binding sites in 80% of the cases. The role of these low-surface-energy areas during complex formation is discussed. Burial of these regions during protein-protein association may favor the complexed configurations with near-native interfaces but otherwise arbitrary orientations, thus driving the formation of an encounter complex. The patch prediction procedure is freely accessible at http://www.molsoft.com/oda and can be easily scaled up for predictions in structural proteomics.

Binding Sites↗

PubMed2005

Differential phospholipase C activation by phenylalkylamine serotonin 5-HT 2A receptor agonists.

Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT 2A receptors. The (+/-)phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT 2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)- and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies. In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT 2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered.

Animals↗

PubMed2002

Protein design from in silico dynamic information: the emergence of the 'turn-dock-lock' motif.

A protein design methodology based on ab initio folding simulations is described and illustrated. First, the time evolution of the chain topology is generated to identify a collapse-triggering nucleus. Then, a minimal spliced sequence of nuclear residues is created and systematically mutated in silico until it can sustain a stable conformation retaining the original nucleus topology. The mutations introduce a structural compensation for the deletions and eventually lead to the recovery of the native fold motif beyond topological identity. For ubiquitin, the systematically modified sequence is predicted to be a resilient folder, since it is 92% homologous to the hyperthermophile variant of B1-domain in streptococcal protein G. The methodology enabling us to identify the nucleus is independently validated vis-á-vis site-directed mutagenesis experiments on chymotrypsin inhibitor (CI2).

Algorithms↗

PubMed2001

Enantioselectivity of some 1-[(benzofuran-2-yl) phenylmethyl] imidazoles as aromatase (P450AROM) inhibitors.

The enantioselectivity ratio ((+)-:(-)-forms) of three substituted 1-[(benzofuran-2-yl) phenylmethyl] imidazoles as inhibitors of aromatase (P450AROM) was 2.16, 12.3 and 1.0 for the 4-methyl-, 4-fluoro- and 4-chloro-substituted compounds, respectively. The (+/-)-compounds were all >1000 times more potent than (+/-)-aminoglutethimide (IC50 = 12 x 10(3) nM). High potency (5.3-65.0 nM) for all the enantiomers studied is unusual since activity usually resides in one form for chiral inhibitors of P450AROM. The 4-methyl derivative was fitted into the model [Furet, P., Batzl, C., Bhatnager, A.S., Francotte, E., Rihs, G. and Lang, M. (1993) J. Med. Chem. 36, pp. 1393-1400] for binding of S-(-)-fadrazole to the active site and the (R)- and (S)- forms both gave a good fitting pattern with (S)-(-)-fadrazole so accounting for their close activity. Docking of both forms into the active site model for P450AROM [Laughton, C.A., Zvelebil, M.J.J.M. and Neidel, S. (1993) J. Steroid Biochem. Mol. Biol. 44, pp. 399-407], using the orientation of (S)-(-)-fadrazole, gave similar strong binding along the position of the C and D rings of the steroid substrate and in the hydrophobic cavity below the A/B rings. The site was probed for group size accommodation using the less potent 4-phenyl analogue (IC50(+/-) = 242 nM): the (S)-form showed restricted access to the region under the A ring due to the extended bulk of the biphenyl group.

Animals↗

PubMed1994

Solution structure of bound trimethoprim in its complex with Lactobacillus casei dihydrofolate reductase.

Two- and three-dimensional (2D and 3D) NMR techniques have been used to assign the signals from nearly all of the protons in Lactobacillus casei dihydrofolate reductase (DHFR) (M(r) 18,300) in its 1:1 complex with the antibacterial drug trimethoprim. A sample of uniformly 15N-labeled protein was examined using 3D 15N/1H experiments [nuclear Overhauser, heteronuclear multiple quantum coherence (NOESY-HMQC) and total correlation, heteronuclear multiple quantum coherence (TOCSY-HMQC) experiments]. Twenty-two intermolecular NOEs between trimethoprim and protein protons and four intramolecular NOEs in the ligand have been detected. Some were obtained by using heteronuclear editing and 2D HMQC-NOESY experiments on complexes formed with 15N-and 13C-labeled trimethoprim molecules ([1,3-15N2,2-amino-15N]-and [7-13C,4'-methoxy-13C]trimethoprim) bound to unlabeled protein. The ligand-protein NOEs were used as distance constraints in conjunction with minimum energy and simulated annealing calculations (carried out with X-PLOR) to dock the trimethoprim ligand into dihydrofolate reductase, using as a starting structure the crystal coordinates from a related complex with a similar overall protein structure. The restrained minimum energy calculations and the simulated annealing calculations gave 83 calculated structures with distance violations of < 0.1 A. In all of these, the two aromatic rings of trimethoprim occupied essentially the same region of conformational space in the binding site (RMSD = 0.63 A). The protein residues nearest to the bound trimethoprim were found to be very similar in all of the structures and agreed well with corresponding contact residues observed in the X-ray crystal studies on trimethoprim complexes formed with Escherichia coli and chicken liver DHFRs.

Amino Acid Sequence↗

PubMed2001

Prediction of potential toxicity and side effect protein targets of a small molecule by a ligand-protein inverse docking approach.

Determination of potential drug toxicity and side effect in early stages of drug development is important in reducing the cost and time of drug discovery. In this work, we explore a computer method for predicting potential toxicity and side effect protein targets of a small molecule. A ligand-protein inverse docking approach is used for computer-automated search of a protein cavity database to identify protein targets. This database is developed from protein 3D structures in the protein data bank (PDB). Docking is conducted by a procedure involving multiple conformer shape-matching alignment of a molecule to a cavity followed by molecular-mechanics torsion optimization and energy minimization on both the molecule and the protein residues at the binding region. Potential protein targets are selected by evaluation of molecular mechanics energy and, while applicable, further analysis of its binding competitiveness against other ligands that bind to the same receptor site in at least one PDB entry. Our results on several drugs show that 83% of the experimentally known toxicity and side effect targets for these drugs are predicted. The computer search successfully predicted 38 and missed five experimentally confirmed or implicated protein targets with available structure and in which binding involves no covalent bond. There are additional 30 predicted targets yet to be validated experimentally. Application of this computer approach can potentially facilitate the prediction of toxicity and side effect of a drug or drug lead.

Ascorbic Acid↗

PubMed1997

Lead discovery of inhibitors of the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase.

A three-dimensional structure model of the dihydrofolate reductase (DHFR) domain of the bifunctional DHFR-thymidylate synthase of Plasmodium falciparum was used as a basis for computational screening of commercially available compounds for candidate inhibitors. Compounds which can stably dock to the model with strong ionic hydrogen bonds via protonation by an aspartic acid residue at the bottom of the active site were identified through docking simulation. Among compounds thus identified, 21 were assayed for inhibitory activity towards the recombinant DHFR domain. Two compounds, 2-amino-1,4-dihydro-4,4,7,8-tetramethyl-s-triazino(1,2-a)benzimida zole and Trp-P-2, inhibited the recombinant P. falciparum DHFR domain with Ki values of 0.54 and 8.7 microM, respectively. Kinetic analysis showed that these compounds competitively inhibited the enzyme with respect to the substrate dihydrofolate. These findings support the validity of both the modeled structure and the docking results. Furthermore, these compounds serve as leads for developing new DHFR inhibitors, since their skeletal structures are different from any of known DHFR inhibitors. This paper also reveals a new biological activity of Trp-P-2, a potent mutagen.

Animals↗

PubMed2004

Active site binding modes of the beta-diketoacids: a multi-active site approach in HIV-1 integrase inhibitor design.

Predicting a bioactive conformation of a ligand is of paramount importance in rational drug design. The task becomes very difficult when the receptor site possesses a region with unusual conformational flexibility. Significant conformational differences are present in the active site regions in the available crystal structures of the core domains of HIV-1 integrase (IN). Among all reported IN inhibitors, the beta-diketoacid class of compounds has proved to be of most promise and indeed S-1360 was the first IN inhibitor to enter clinical studies. With an aim to predict the bioactive (active site bound) conformation of S-1360, we performed extensive docking studies using three different reported crystal structures where the active site or partial active site region was resolved. For comparison we extended our studies to include 5CITEP (the first compound cocrystallized with IN core domain) and a bis-diketoacid (BDKA). We found that the conformation of S-1360 when bound in one of the active sites matches that of the experimentally observed results of IN escape mutants resistant to S-1360. Therefore, we propose that this active site conformation is the biologically relevant conformation and can be used for the future structure-based drug design studies selectively targeting IN.

Anti-HIV Agents↗

PubMed2002

Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex.

Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor. The structural similarity between telomestatin and a G-tetrad suggested to us that the telomerase inhibition might be due to its ability either to facilitate the formation of or trap out preformed G-quadruplex structures, and thereby sequester single-stranded d[T(2)AG(3)](n) primer molecules required for telomerase activity. Significantly, telomestatin appears to be a more potent inhibitor of telomerase (5 nM) than any of the previously described G-quadruplex-interactive molecules. In this communication we provide the first experimental evidence that telomestatin selectively facilitates the formation of or stabilizes intramolecular G-quadruplexes, in particular, that produced from the human telomeric sequence d[T(2)AG(3)](4). A simulated annealing (SA) docking approach was used to study the binding interactions of telomestatin with the intramolecular antiparallel G-quadruplex structure. Each intramolecular G-quadruplex molecule was found to bind two telomestatin molecules (unpublished results). A 2:1 model for the telomestatin bound in the external stacking mode in an energy minimized complex with the human telomeric basket-type G-quadruplex was constructed. Our observation that a G-quadruplex-interactive molecule without significant groove interactions is able to reorient in a G-quadruplex structure proints to the importance of core interaction with an asymmetric G-quadruplex structure in producing selective binding. Furthermore, the G-quadruplex interactions of telomestatin are more selective for the intramolecular structure in contrast to other G-quadruplex-interactive agents, such as TMPyP4.

DNA↗

PubMed2002

Protein Alpha Shape Similarity Analysis (PASSA): a new method for mapping protein binding sites. Application in the design of a selective inhibitor of tyrosine kinase 2.

We have developed a method that we have called Protein Alpha Shape Similarity Analysis (PASSA), that identifies interaction sites that can be utilised to achieve selectivity towards a protein. We have shown that this method is able to identify residues of tyrosine kinases that interact with known selective inhibitors using the following test cases: Abelson (Abl) kinase in complex with STI-571 and Janus kinase 2 (Jak2) in complex with AG-490. The 3D structures of the tyrosine kinase domains of Tyrosine kinase 2 (Tyk2) and Jak2 have been predicted by homology modelling. Computational docking of AG-490 and a set of tyrphostins known not to inhibit Jak2 indicated that our homology models are able to separate inhibitors from non-inhibitors. PASSA has also been used to identify unique properties of Tyk2. According to our results, interactions with hydrogen acceptors and donors on the following residues can be utilised to achieve selectivity towards Tyk2: Y955, E1053, D1062 and S1063. These residues are placed close to non-conserved hydrophobic pockets. The PASSA results, together with results from Multiple Copy Simultaneous Search (MCSS) were used to suggest functional groups of a selective Tyk2 inhibitor.

Amino Acid Sequence↗

PubMed2001

Platelet-derived growth factor-BB and basic fibroblast growth factor directly interact in vitro with high affinity.

Platelet-derived growth factor-BB (PDGF-BB) and basic fibroblast growth factor (bFGF) are potent growth factors active on many cell types. The present study indicates that they directly interact in vitro. The interaction was investigated with overlay experiments, surface plasmon resonance experiments, and solid-phase immunoassays by immobilizing one factor or the other and by steady-state fluorescence analysis. The interaction observed was specific, dose-dependent, and saturable, and the bFGF/PDGF-BB binding stoichiometry was found to be 2:1. K(D)(1) for the first step equilibrium and the overall K(D) values were found to be in the nanomolar and in the picomolar range, respectively. Basic FGF/PDGF-BB interaction was strongly reduced as a function of time of PDGF-BB proteolysis. Furthermore, docking analysis suggested that the PDGF-BB region interacting with bFGF may overlap, at least in part, with the PDGF-BB receptor-binding site. This hypothesis was supported by surface plasmon resonance experiments showing that an anti-PDGF-BB antibody, known to inhibit PDGF-BB binding with its receptor, strongly reduced bFGF/PDGF-BB interaction, whereas a control antibody was ineffective. According to these data, the observed bFGF.PDGF-BB complex formation might explain, at least in part, previous observations showing that PDGF-BB chemotactic and mitogenic activity on smooth muscle cells are strongly inhibited in the presence of bFGF.

Becaplermin↗

PubMed2006

A domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks.

BACKGROUND: Receptors and scaffold proteins possess a number of distinct domains and bind multiple partners. A common problem in modeling signaling systems arises from a combinatorial explosion of different states generated by feasible molecular species. The number of possible species grows exponentially with the number of different docking sites and can easily reach several millions. Models accounting for this combinatorial variety become impractical for many applications. RESULTS: Our results show that under realistic assumptions on domain interactions, the dynamics of signaling pathways can be exactly described by reduced, hierarchically structured models. The method presented here provides a rigorous way to model a large class of signaling networks using macro-states (macroscopic quantities such as the levels of occupancy of the binding domains) instead of micro-states (concentrations of individual species). The method is described using generic multidomain proteins and is applied to the molecule LAT. CONCLUSION: The presented method is a systematic and powerful tool to derive reduced model structures describing the dynamics of multiprotein complex formation accurately.

Binding Sites↗

PubMed1999

Database screening for HIV protease ligands: the influence of binding-site conformation and representation on ligand selectivity.

Screening for potential ligands and docking them into the binding sites of proteins is one of the main tasks in computer-aided drug design. Despite the progress in computational power, it remains infeasible to model all the factors involved in molecular recognition, especially when screening databases of more than 100,000 compounds. While ligand flexibility is considered in most approaches, the model of the binding site is rather simplistic, with neither solvation nor induced complementary usually taken into consideration. We present results for screening different databases for HIV-1 protease ligands with our tool Slide, and investigate the extent to which binding-site conformation, solvation, and template representation generate bias. The results suggest a strategy for selecting the optimal binding-site conformation, for cases in which more than one independent structure is available, and selecting a representation of that binding site that yields reproducible results and the identification of known ligands.

Binding Sites↗

PubMed2002

Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels.

The recognition of the scorpion toxin maurotoxin (MTX) by the voltage-gated potassium (Kv1) channels, Kv1.1, Kv1.2, and Kv1.3, has been studied by means of Brownian dynamics (BD) simulations. All of the 35 available structures of MTX in the Protein Data Bank (http://www.rcsb.org/pdb) determined by nuclear magnetic resonance were considered during the simulations, which indicated that the conformation of MTX significantly affected both the recognition and the binding between MTX and the Kv1 channels. Comparing the top five highest-frequency structures of MTX binding to the Kv1 channels, we found that the Kv1.2 channel, with the highest docking frequencies and the lowest electrostatic interaction energies, was the most favorable for MTX binding, whereas Kv1.1 was intermediate, and Kv1.3 was the least favorable one. Among the 35 structures of MTX, the 10th structure docked into the binding site of the Kv1.2 channel with the highest probability and the most favorable electrostatic interactions. From the MTX-Kv1.2 binding model, we identified the critical residues for the recognition of these two proteins through triplet contact analyses. MTX locates around the extracellular mouth of the Kv1 channels, making contacts with its beta-sheets. Lys23, a conserved amino acid in the scorpion toxins, protrudes into the pore of the Kv1.2 channel and forms two hydrogen bonds with the conserved residues Gly401(D) and Tyr400(C) and one hydrophobic contact with Gly401(C) of the Kv1.2 channel. The critical triplet contacts for recognition between MTX and the Kv1.2 channel are Lys23(MTX)-Asp402(C)(Kv1), Lys27(MTX)-Asp378(D)(Kv1), and Lys30(MTX)-Asp402(A)(Kv1). In addition, six hydrogen-bonding interactions are formed between residues Lys23, Lys27, Lys30, and Tyr32 of MTX and residues Gly401, Tyr400, Asp402, Asp378, and Thr406 of Kv1.2. Many of them are formed by side chains of residues of MTX and backbone atoms of the Kv1.2 channel. Five hydrophobic contacts exist between residues Pro20, Lys23, Lys30 and Tyr32 of MTX and residues Asp402, Val404, Gly401, and Arg377 of the Kv1.2 channel. The simulation results are in agreement with the previous molecular biology experiments and explain the binding phenomena between MTX and Kv1 channels at the molecular level. The consistency between the results of the BD simulations and the experimental data indicated that our three-dimensional model of the MTX-Kv1.2 channel complex is reasonable and can be used in additional biological studies, such as rational design of novel therapeutic agents blocking the voltage-gated channels and in mutagenesis studies in both the toxins and the Kv1 channels. In particular, both the BD simulations and the molecular mechanics refinements indicate that residue Asp378 of the Kv1.2 channel is critical for its recognition and binding functionality toward MTX. This phenomenon has not been appreciated in the previous mutagenesis experiments, indicating this might be a new clue for additional functional study of Kv1 channels.

Amino Acid Motifs↗

PubMed2002

Flexible docking under pharmacophore type constraints.

FLEXX-PHARM, an extended version of the flexible docking tool FLEXX, allows the incorporation of information about important characteristics of protein-ligand binding modes into a docking calculation. This information is introduced as a simple set of constraints derived from receptor-based type pharmacophore features. The constraints are determined by selected FLEXX interactions and inclusion volumes in the receptor active site. They guide the docking process to produce a set of docking solutions with particular properties. By applying a series of look-ahead checks during the flexible construction of ligand fragments within the active site, FLEXX-PHARM determines which partially built docking solutions can potentially obey the constraints. Solutions that will not obey the constraints are deleted as early as possible, often decreasing the calculation time and enabling new docking solutions to emerge. FLEXX-PHARM was evaluated on various individual protein-ligand complexes where the top docking solutions generated by FLEXX had high root mean square deviations (RMSD) from the experimentally observed binding modes. FLEXX-PHARM showed an improvement in the RMSD of the top solutions in most cases, along with a reduction in run time. We also tested FLEXX-PHARM as a database screening tool on a small dataset of molecules for three target proteins. In two cases, FLEXX-PHARM missed one or two of the active molecules due to the constraints selected. However, in general FLEXX-PHARM maintained or improved the enrichment shown with FLEXX, while completing the screen in considerably less run time.

Algorithms↗

PubMed2003

Computer-aided design of a factor Xa inhibitor by using MCSS functionality maps and a CAVEAT linker search.

We have investigated a new approach to efficiently find a novel inhibitor against a serine protease (i.e. an activated coagulation factor X, FXa) by using de novo design programs and the X-ray crystal structure of the target enzyme. FXa is a coagulant enzyme that generates thrombin (a serine protease) and participates in both intrinsic and extrinsic coagulation pathways. We adopted multiple copy simultaneous search (MCSS) and CAVEAT linker search techniques, which disclosed a novel FXa inhibitor (T01312) consisting of two binding moieties (the benzamidinyl and adamantyl groups) and a linker unit (the carboxybenzylamine group). The inhibitory activity of T01312 against FXa was determined to be a small K(i)-value of 48nM, which is two orders of magnitude smaller than that against thrombin. An X-ray crystal analysis of T01312 complexed with trypsin (an analogue of FXa) and docking studies of T01312 with trypsin and FXa showed that: (i) the benzamidinyl group is a predominant binding moiety in the anionic pocket (S1 site) with an asparatic acid residue; (ii) a hydrophobic pocket (S4 site) is the binding site of the adamantyl group; (iii) the carboxylate group of the linker contributes to the selectivity for FXa against thrombin. Thus, the combination of the knowledge of the X-ray crystal structure of the target molecule with MCSS and CAVEAT linker search techniques proved to be an effective hit-finding method that does not require the screening of huge compound libraries.

Antithrombin III↗