| 1. |
- Chen, Zhen, et al.
(författare)
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Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton
- 2019
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 62:7, s. 3336-3353
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Tidskriftsartikel (refereegranskat)abstract
- Monoacylglycerol lipase (MAGL) is a senile hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with C-11 or F-18. [C-11]8 ([C-11]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [C-11]17 ([C-11]PAD) and [F-18]37 ([F-18]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
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| 2. |
- Nam, Kwangho, et al.
(författare)
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Perspectives on computational enzyme modeling : from mechanisms to design and drug development
- 2024
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 9:7, s. 7393-7412
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Forskningsöversikt (refereegranskat)abstract
- Understanding enzyme mechanisms is essential for unraveling the complex molecular machinery of life. In this review, we survey the field of computational enzymology, highlighting key principles governing enzyme mechanisms and discussing ongoing challenges and promising advances. Over the years, computer simulations have become indispensable in the study of enzyme mechanisms, with the integration of experimental and computational exploration now established as a holistic approach to gain deep insights into enzymatic catalysis. Numerous studies have demonstrated the power of computer simulations in characterizing reaction pathways, transition states, substrate selectivity, product distribution, and dynamic conformational changes for various enzymes. Nevertheless, significant challenges remain in investigating the mechanisms of complex multistep reactions, large-scale conformational changes, and allosteric regulation. Beyond mechanistic studies, computational enzyme modeling has emerged as an essential tool for computer-aided enzyme design and the rational discovery of covalent drugs for targeted therapies. Overall, enzyme design/engineering and covalent drug development can greatly benefit from our understanding of the detailed mechanisms of enzymes, such as protein dynamics, entropy contributions, and allostery, as revealed by computational studies. Such a convergence of different research approaches is expected to continue, creating synergies in enzyme research. This review, by outlining the ever-expanding field of enzyme research, aims to provide guidance for future research directions and facilitate new developments in this important and evolving field.
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| 3. |
- Shao, Yihan, et al.
(författare)
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Benchmarking the Performance of Time-Dependent Density Functional Theory Methods on Biochromophores
- 2020
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 16:1, s. 587-600
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Tidskriftsartikel (refereegranskat)abstract
- Quantum chemical calculations are important for elucidating light-capturing mechanisms in photobiological systems. The time-dependent density functional theory (TDDFT) has become a popular methodology because of its balance between accuracy and computational scaling, despite its problems in describing, for example, charge transfer states. As a step toward systematically understanding the performance of TDDFT calculations on biomolecular systems, we study here 17 commonly used density functionals, including seven long-range separated functionals, and compare the obtained results with excitation energies calculated at the approximate second order coupled-cluster theory level (CC2). The benchmarking set includes the first five singlet excited states of 11 chemical analogues of biochromophores from the green fluorescent protein, rhodopsin/bacteriorhodopsin (Rh/bR), and the photoactive yellow protein. We find that commonly used pure density functionals such as BP86, PBE, M11-L, and hybrid functionals with 20-25% of Hartree-Fock (HF) exchange (B3LYP, PBE0) have a tendency to consistently underestimate vertical excitation energies (VEEs) relative to the CC2 values, whereas hybrid density functionals with around 50% HF exchange such as BHLYP, PBE50, and M06-2X and long-range corrected functionals such as CAM-B3LYP, omega PBE, omega PBEh, omega B97X, omega B97XD, BNL, and M11 overestimate the VEEs. We observe that calculations using the CAM-B3LYP and omega PBEh functionals with 65% and 100% long-range HF exchange, respectively, lead to an overestimation of the VEEs by 0.2-0.3 eV for the benchmarking set. To reduce the systematic error, we introduce here two new empirical functionals, CAMh-B3LYP and omega hPBE0, for which we adjusted the long-range HF exchange to 50%. The introduced parameterization reduces the mean signed average (MSA) deviation to 0.07 eV and the root mean square (rms) deviation to 0.17 eV as compared to the CC2 values. In the present study, TDDFT calculations using the aug-def2-TZVP basis sets, the best performing functionals relative to CC2 are omega hPBE0 (rms = 0.17, MSA = 0.06 eV); CAMh-B3LYP (rms = 0.16, MSA = 0.07 eV); and PBE0 (rms = 0.23, MSA = 0.14 eV). For the popular range-separated CAM-B3LYP functional, we obtain an rms value of 0.31 eV and an MSA value of 0.25 eV, which can be compared with the rms and MSA values of 0.37 and -0.31 eV, respectively, as obtained at the B3LYP level.
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