scholarly journals Construction of a Full-Atomic Mechanistic Model of Human Apurinic/Apyrimidinic Endonuclease APE1 for Virtual Screening of Novel Inhibitors

Acta Naturae ◽  
2012 ◽  
Vol 4 (2) ◽  
pp. 80-86
Author(s):  
I. G. Khaliullin ◽  
D. K. Nilov ◽  
I. V. Shapovalova ◽  
V. K. Švedas
Keyword(s):  
Experimental Data ◽  
Active Site ◽  
Molecular Model ◽  
Mechanistic Model ◽  
Proton Acceptor ◽  
Repair System ◽  
Amino Acid Residues ◽  
Enzyme Substrate ◽  
Oncological Diseases ◽  
Important Enzyme

A full-atomic molecular model of human apurinic/apyrimidinic endonuclease APE1, an important enzyme in the DNA repair system, has been constructed. The research consisted of hybrid quantum mechanics/ molecular mechanics modeling of the enzyme-substrate interactions, as well as calculations of the ionization states of the amino acid residues of the active site of the enzyme. The choice of the APE1 mechanism with an Asp210 residue as a proton acceptor was validated by means of a generalization of modeling and experimental data. Interactions were revealed in the active site that are of greatest significance for binding the substrate and potential APE1 inhibitors (potential co-drugs of interest in the chemo- and radiotherapy of oncological diseases).

scholarly journals Construction of a Full-Atomic Mechanistic Model of Human Apurinic/Apyrimidinic Endonuclease APE1 for Virtual Screening of Novel Inhibitors

Acta Naturae ◽  
2012 ◽  
Vol 4 (2) ◽  
pp. 80-86 ◽  
Author(s):  
I. G. Khaliullin ◽  
D. K. Nilov ◽  
I. V. Shapovalova ◽  
V. K. Švedas
Keyword(s):  
Experimental Data ◽  
Active Site ◽  
Molecular Model ◽  
Mechanistic Model ◽  
Proton Acceptor ◽  
Repair System ◽  
Amino Acid Residues ◽  
Enzyme Substrate ◽  
Oncological Diseases ◽  
Important Enzyme

A full-atomic molecular model of human apurinic/apyrimidinic endonuclease APE1, an important enzyme in the DNA repair system, has been constructed. The research consisted of hybrid quantum mechanics/ molecular mechanics modeling of the enzyme-substrate interactions, as well as calculations of the ionization states of the amino acid residues of the active site of the enzyme. The choice of the APE1 mechanism with an Asp210 residue as a proton acceptor was validated by means of a generalization of modeling and experimental data. Interactions were revealed in the active site that are of greatest significance for binding the substrate and potential APE1 inhibitors (potential co-drugs of interest in the chemo- and radiotherapy of oncological diseases).

THEORY OF THE TRANSIENT PHASE IN AN ENZYME SYSTEM INVOLVING TWO ENZYME-SUBSTRATE COMPLEXES: THE CASE OF THE FORMATION OF PRODUCTS FROM THE FIRST COMPLEX

1959 ◽  
Vol 37 (4) ◽  
pp. 737-743 ◽  
Author(s):  
Ludovic Ouellet ◽  
James A. Stewart
Keyword(s):  
Experimental Data ◽  
Steady State ◽  
Active Site ◽  
Substrate Concentration ◽  
Enzyme System ◽  
Kinetic Scheme ◽  
Enzyme Concentration ◽  
Theoretical Treatment ◽  
Transient Phase ◽  
Enzyme Substrate

A theoretical treatment is worked out for the kinetic scheme[Formula: see text]in which the concentration of P1 is followed. The steady-state and transient phase equations are obtained subject to the condition that the substrate concentration is greatly in excess of the enzyme concentration. The conditions under which evidence in favor of this mechanism can be obtained from experimental data are discussed. Under certain conditions, the weight of the enzyme corresponding to one active site can be determined. Methods for the evaluation of the different constants are described.

scholarly journals Uncovering the Binding Mode of γ-Secretase Inhibitors

2019 ◽  
Author(s):  
M. Hitzenberger ◽  
M. Zacharias
Keyword(s):  
Experimental Data ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Active Site ◽  
Structural Model ◽  
Ph Value ◽  
Binding Mode ◽  
Enzyme Substrate ◽  
Transition State Geometry ◽  
The Stability

AbstractKnowledge of how transition state inhibitors bind to γ-secretase is of major importance for the design of new Alzheimer’s disease therapies. Based on the known structure of γ-secretase in complex with a fragment of the amyloid precursor protein we have generated a structural model of γ-secretase in complex with the effective L-685,458 transition state inhibitor. The predicted binding mode is in excellent agreement with experimental data, mimicking all enzyme-substrate interactions at the active site and forming the relevant transition state geometry with the active site aspartate residues. In addition, we found that the stability of the complex is very likely also sensitive to the pH value. Comparative simulations on the binding of L-685,458 and the epimer L682,679 allowed us to explain the strongly reduced affinity of the epimer for γ-secretase. The structural model could form a valuable basis for the design of new or modified γ-secretase inhibitors.

scholarly journals Structure Modeling of Human TyrosylDNA Phosphodiesterase 1 and Screening for Its Inhibitors

Acta Naturae ◽  
2017 ◽  
Vol 9 (2) ◽  
pp. 59-66 ◽  
Author(s):  
I. V. Gushchina ◽  
D. K. Nilov ◽  
A. L. Zakharenko ◽  
O. I. Lavrik ◽  
V. K. Švedas
Keyword(s):  
Amino Acid ◽  
Active Site ◽  
Molecular Model ◽  
Sulfo Group ◽  
Anticancer Therapy ◽  
Molecular Target ◽  
Structure Modeling ◽  
Amino Acid Residues ◽  
Repair Enzyme ◽  
Competitive Inhibitors

The DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) represents a potential molecular target for anticancer therapy. A human Tdp1 model has been constructed using the methods of quantum and molecular mechanics, taking into account the ionization states of the amino acid residues in the active site and their interactions with the substrate and competitive inhibitors. The oligonucleotide- and phosphotyrosine-binding cavities important for the inhibitor design have been identified in the enzymes active site. The developed molecular model allowed us to uncover new Tdp1 inhibitors whose sulfo group is capable of occupying the position of the 3-phosphate group of the substrate and forming hydrogen bonds with Lys265, Lys495, and other amino acid residues in the phosphotyrosine binding site.

Creating lipoxygenases with new positional specificities by site-directed mutagenesis

2000 ◽  
Vol 28 (6) ◽  
pp. 825-826 ◽  
Author(s):  
E. Hornung ◽  
S. Rosahl ◽  
H. Kühn ◽  
I. Feussner
Keyword(s):  
Amino Acid ◽  
Active Site ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Sequence Alignments ◽  
Positional Specificity ◽  
The Past ◽  
Enzyme Substrate ◽  
Plant Lipoxygenases

In order to analyse the amino acid determinants which alter the positional specificity of plant lipoxygenases (LOXs), multiple LOX sequence alignments and structural modelling of the enzyme-substrate interactions were carried out. These alignments suggested three amino acid residues as the primary determinants of positional specificity. Here we show the generation of two plant LOXs with new positional specificities, a Δ-linoleneate 6-LOX and an arachidonate 11-LOX, by altering only one of these determinants within the active site of two plant LOXs. In the past, site-directed-mutagenesis studies have mainly been carried out with mammalian lipoxygenases (LOXs) [1]. In these experiments two regions have been identified in the primary structure containing sequence determinants for positional specificity. Amino acids aligning with the Sloane determinants [2] are highly conserved among plant LOXs. In contrast, there is amino acid hetero-geneity among plant LOXs at the position that aligns with P353 of the rabbit reticulocyte 15-LOX (Borngräber determinants) [3].

scholarly journals trans-3-Chloroacrylic Acid Dehalogenase from Pseudomonas pavonaceae 170 Shares Structural and Mechanistic Similarities with 4-Oxalocrotonate Tautomerase

2001 ◽  
Vol 183 (14) ◽  
pp. 4269-4277 ◽  
Author(s):  
Gerrit J. Poelarends ◽  
Raymond Saunier ◽  
Dick B. Janssen
Keyword(s):  
Amino Acid ◽  
Sequence Similarity ◽  
Site Directed Mutagenesis ◽  
Proton Acceptor ◽  
Hydrolytic Cleavage ◽  
Amino Acid Residues ◽  
Active Site Residues ◽  
Α Subunit ◽  
Enzyme Substrate ◽  
Chloroacrylic Acid Dehalogenase

ABSTRACT The genes (caaD1 and caaD2) encoding the trans-3-chloroacrylic acid dehalogenase (CaaD) of the 1,3-dichloropropene-utilizing bacterium Pseudomonas pavonaceae 170 were cloned and heterologously expressed in Escherichia coli andPseudomonas sp. strain GJ1. CaaD is a protein of 50 kDa that is composed of α-subunits of 75 amino acid residues and β-subunits of 70 residues. It catalyzes the hydrolytic cleavage of the β-vinylic carbon-chlorine bond intrans-3-chloroacrylic acid with a turnover number of 6.4 s−1. On the basis of sequence similarity, oligomeric structure, and subunit size, CaaD appears to be related to 4-oxalocrotonate tautomerase (4-OT). This tautomerase consists of six identical subunits of 62 amino acid residues and catalyzes the isomerization of 2-oxo-4-hexene-1,6-dioate, via hydroxymuconate, to yield 2-oxo-3-hexene-1,6-dioate. In view of the oligomeric architecture of 4-OT, a trimer of homodimers, CaaD is postulated to be a hexameric protein that functions as a trimer of αβ-dimers. The sequence conservation between CaaD and 4-OT and site-directed mutagenesis experiments suggested that Pro-1 of the β-subunit and Arg-11 of the α-subunit are active-site residues in CaaD. Pro-1 could act as the proton acceptor/donor, and Arg-11 is probably involved in carboxylate binding. Based on these findings, a novel dehalogenation mechanism is proposed for the CaaD-catalyzed reaction which does not involve the formation of a covalent enzyme-substrate intermediate.

Application of a dynamic mechanistic model of small intestinal starch digestion in the dairy cow

2002 ◽  
Vol 2002 ◽  
pp. 104-104
Author(s):  
J. A. N. Mills ◽  
E. Kebreab ◽  
L. A. Crompton ◽  
J. Dijkstra ◽  
J. France
Keyword(s):  
Experimental Data ◽  
Small Intestine ◽  
Dairy Cow ◽  
Energy Recovery ◽  
Mechanistic Model ◽  
Biological Knowledge ◽  
Dietary Energy ◽  
Starch Digestion ◽  
High Contribution ◽  
Small Intestinal

The high contribution of postruminal starch digestion (>50%) to total tract starch digestion on certain energy dense diets (Mills et al. 1999) demands that limitations to small intestinal starch digestion are identified. Therefore, a dynamic mechanistic model of the small intestine was constructed and evaluated against published experimental data for abomasal carbohydrate infusions in the dairy cow. The mechanistic structure of the model allowed the current biological knowledge to be integrated into a system capable of identifying restrictions to dietary energy recovery from postruminal starch delivery.

A New Dynamic Wettability-Alteration Model for Oil-Wet Cores During Surfactant-Solution Imbibition

SPE Journal ◽  
2013 ◽  
Vol 18 (05) ◽  
pp. 818-828 ◽  
Author(s):  
M. Hosein Kalaei ◽  
Don W. Green ◽  
G. Paul Willhite
Keyword(s):  
Experimental Data ◽  
Oil Recovery ◽  
History Matching ◽  
Mechanistic Model ◽  
Surfactant Solution ◽  
Experimental Tests ◽  
Quantitative Agreement ◽  
Wettability Alteration ◽  
Porous Rock ◽  
Surfactant Solutions

Summary Wettability modification of solid rocks with surfactants is an important process and has the potential to recover oil from reservoirs. When wettability is altered by use of surfactant solutions, capillary pressure, relative permeabilities, and residual oil saturations change wherever the porous rock is contacted by the surfactant. In this study, a mechanistic model is described in which wettability alteration is simulated by a new empirical correlation of the contact angle with surfactant concentration developed from experimental data. This model was tested against results from experimental tests in which oil was displaced from oil-wet cores by imbibition of surfactant solutions. Quantitative agreement between the simulation results of oil displacement and experimental data from the literature was obtained. Simulation of the imbibition of surfactant solution in laboratory-scale cores with the new model demonstrated that wettability alteration is a dynamic process, which plays a significant role in history matching and prediction of oil recovery from oil-wet porous media. In these simulations, the gravity force was the primary cause of the surfactant-solution invasion of the core that changed the rock wettability toward a less oil-wet state.

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