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Chemistry-led investigations into the mode of action of NAMPT activators,resulting in the discovery of non-pyridyl class NAMPT activators

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Acta Pharmaceutica Sinica B 2023年第2期13卷 709-721页

作者： Siyuan Tang miguel garzon sanz Oliver Smith Andreas Krämer Daniel Egbase Paul W.Caton Stefan Knapp Sam Butterworth Division of Pharmacy and Optometry School of Health SciencesManchester Academic Health Sciences CentreUniversity of ManchesterManchester M139PLUK Structural Genomics Consortium(SGC) 60438 Frankfurt Am MainGermany Buchmann Institute for Life Sciences(BMLS) 60438 Frankfurt Am MainGermany Institut für Pharmazeutische Chemie Goethe University60438 Frankfurt Am MainGermany Frankfurt Cancer Institute(FCI) 60596 Frankfurt Am MainGermany Department of Diabetes School of Cardiovascular and Metabolic Medicine&SciencesFaculty of Life Sciences&MedicineKing's College LondonLondon SE11ULUK

The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.

关键词： Nicotinamide phosphoribosyl transferase activator Healthy aging Drug discovery Bioisosteres Medicinal chemistry

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Analysis of Bone Remodeling Under Piezoelectricity Effects Using Boundary Elements

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Journal of Bionic Engineering 2017年第4期14卷 659-671页

作者： miguel Cerrolaza Vannessa Duarte Diego garzon-Alvarado National Institute of Bioengineering Central University of Venezuela Caracas Venezuela International Center for Numerical Methods in Engineering ( CIMNE) Polytechnic University of Catalonia Barcelona Spain Virtual Rooms Program ( CIMNE) Polytechnic University of Catalonia Barcelona Spain Laboratory of Biomimetics Group of Mechanobiology of Organs and Tissues Biotechnology Institute Department of Mechanical Engineering and Mechatronics National University of Colombia Bogota Colombia

Piezoelectric materials exhibit a response to mechanical-electrical coupling, which represents an important contribution to the electrical-mechanical interaction in bone remodeling process. Therefore, the study of the piezoelectric effect on bone re- modeling has high interest in applied biomechanics. The effects of mechano-regulation and electrical stimulation on bone healing are explained. The Boundary Element Method （BEM） is used to simulate piezoelectric effects on bones when shearing forces are applied to collagen fibers to make them slip past each other. The piezoelectric fundamental solutions are obtained by using the Radon transform. The Dual Reciprocity Method （DRM） is used to simulate the particular solutions in time-dependent problems. BEM analysis showed the strong influence of electrical stimulation on bone remodeling. The examples discussed in this work showed that, as expected, the electrically loaded bone surfaces improved the bone deposition. BEM results confirmed previous findings obtained by using the Finite Element Method （FEM）. This work opens very promising doors in biomechanics research, showing that mechanical loads can be replaced, in part, by electrical charges that stimulate strengthening bone density. The obtained results herein are in good agreement with those found in literature from experimental testing and/or other simu- lation approaches.

关键词： bone remodeling numerical methods piezoelectricity boundary element anisotropy

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