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Kinetics Part 1
Published in Patrick E. McMahon, Rosemary F. McMahon, Bohdan B. Khomtchouk, Survival Guide to General Chemistry, 2019
Patrick E. McMahon, Rosemary F. McMahon, Bohdan B. Khomtchouk
A transition state is a description of atom arrangements showing partial bonds formed or broken for the required molecular changes involved in a reaction step. The partial bonds indicate how the reactant atoms are rearranging to form the correct product molecules.
Introduction to Enzymes
Published in John C. Matthews, Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
By reducing the height of the activation energy barrier enzymes reduce the amount of energy necessary for a molecule to reach the transition state. This allows the reaction to proceed faster at lower temperatures. In this way, enzymes are capable of very large increases in chemical reaction rates. An energy diagram can be compared to a road over a mountain with cities on either side connected by the road. Commodities traveling from one city to the other must be hauled over the mountain by truck. If you have ever followed a loaded truck up a steep mountain grade you have an idea of how difficult obtaining the necessary activation energy can be. Now suppose that the two cities pool their resources and dig a tunnel through the mountain. Trucks are no longer required to climb the steep grades on the way up and wear out their brakes on the way down. Thus, transit between the two cities is quicker and more efficient. The enzyme acts like the tunnel. The source and destination are still the same, but the barrier separating them has changed.
Some Underlying Physical Principles
Published in Clive R. Bagshaw, Biomolecular Kinetics, 2017
The transition state is not an intermediate but a highly unstable state that quickly (within around 10−12 s for true elementary reactions) progresses to product, B. The concentration of molecules in the transition state at any point in time is extremely low. For a reaction with an observed rate constant of 1 s−1, only about 10−12 of the [A] would be in the transition state. This factor, together with their short lifetime, means that the transition state cannot be directly detected or characterized chemically by conventional kinetic methods.
The prediction of protein–ligand unbinding for modern drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Qianqian Zhang, Nannan Zhao, Xiaoxiao Meng, Fansen Yu, Xiaojun Yao, Huanxiang Liu
The development of computer-aided drug design [7] and molecular dynamic (MD) simulations [8] has provided a great complement to experimental methods. Nevertheless, observing protein–ligand dissociation with traditional MD simulations is burdensome because protein–ligand dissociation requires a large amount of conformational sampling and must overcome the high energy barrier that exists between different transition states [9]. Therefore, considerable effort has been expended to develop enhanced sampling methods for the prediction of protein–ligand unbinding. The essential principle of most enhanced sampling methods is to add an external force (such as Steered MD [SMD] [10]) or bias potential (such as Metadynamic [MetaD] [11]) to help a system cross the barrier between energy basins. Some classic unbiased sampling methods, such as weighted ensemble sampling (WES) [12], Markov state modeling (MSM) analysis [13] and adaptive multilevel splitting (AMS) [14], are also available. These biased and unbiased methods have been utilized to study the prediction of the RT, koff and binding free energy of ligands [15–17] extensively. Moreover, the investigation of the protein–ligand dissociation mechanism and transition state [18–20] throughout unbinding is important in rational drug design. Many methods have undergone a series of improvements and have derived many variants to improve prediction accuracy. We will summarize these methods in the next section.
Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450
Published in Drug Metabolism Reviews, 2020
Chaitanya K. Jaladanki, Anuj Gahlawat, Gajanan Rathod, Hardeep Sandhu, Kousar Jahan, Prasad V. Bharatam
QC methods are being widely used to address key questions about CYP450-catalyzed reactions. The information being sought from such analysis includes: (i) the electronic structure of reactants, intermediates, products and transition states; (ii) the absolute and the relative energies of all the species; (iii) the details of molecular orbitals (shapes and energies); (iii) estimation of partial atomic charges, electrophilicity and nucleophilicity parameters; (iv) surface properties (molecular electrostatic potential); (v) reaction pathways, by establishing the energy profiles of the metabolic reactions; (vi) internal surface distribution of electron density, spin density (Gao and Truhlar 2002; Friesner and Guallar 2005; Shaik et al. 2010; Siegbahn and Blomberg 2010; Rydberg et al. 2012; Blomberg et al. 2014; Hirao et al. 2014). The transition states on the enzyme-catalyzed metabolic reaction pathways are central and cannot be studied experimentally owing to their short-lived character (Becke 1993), but the same can be obtained using QC methods with sufficient clarity. Moreover, the interactions stabilizing these transition states cannot be determined by experimental methods. Thus, QC methods are utilized for the overall understanding of the complexities and challenges in drug metabolism studies.
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
N. Kirsch et al. in 2009, reported product analogue imprinted polymer catalyzed Diels-Alder cycloaddition reaction [63] reaction of 1, 3-butadiene carbamic acid benzyl ester and N,N-dimethylacrylamide (Figure 29). Recognized transition state analogues for the endo- and exo-reaction pathways were used as templates for the synthesis of molecularly imprinted methacrylic acid–divinylbenzene copolymers. The recognized transition state is also shown. Batch binding studies revealed that the imprinted polymers were selective for the TSA corresponding to the template used in the polymer synthesis. Studies on the influence of the polymers on the catalysis of the reaction of 1, 3-butadiene carbamic acid benzyl ester and N,N-dimethylacrylamide demonstrated a 20-fold enhancement of the rate of the reaction relative to the solution phase reaction. A surprising temperature dependence of the reaction of 1, 3-butadiene carbamic acid benzyl ester and N,N-dimethylacrylamide in the presence of the polymers was observed, which provides support for the role of template-functional monomer complexes in the catalysis of the Diels-Alder reaction.