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Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months to years. The clinical protocol of CKD forecasts that markers such as serum creatinine, the estimate of the glomerular filtration rate value, microalbuminuria, cystatin c are evaluated as routine markers. In recent years, new studies have identified new markers to diagnose and assess the level of kidney damage.The prevalence of CKD increases in subjects suffering from cardiovascular and metabolic diseases. The highest risk of cardiovascular risk in the CKD patient compared to the general population is related to risk factors such as hypertension, obesity, and specific renal disease factors such as albuminuria.Physical exercise, especially aerobic, has been seen through the analysis of urinary markers, able to mitigate the adverse effect of sedentary, hypertension and interstitial damage in patients with CKD and decrease the urinary levels liver-type fatty acid binding protein (L-FABP) and lower urinary albumin excretion.

In small molecule binding, water is not a passive bystander but rather takes an active role in the binding site, which may be decisive for the potency of the inhibitor. Here, by addressing a high-energy water, we improved the IC50 value of our co-crystallized glycogen synthase kinase-3β (GSK-3β) inhibitor by nearly two orders of magnitude. Surprisingly, our results demonstrate that this high-energy water was not displaced by our potent inhibitor (S)-3-(3-((7-ethynyl-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile ((S)-15, IC50 value of 6 nM). Instead, only a subtle shift in the location of this water molecule resulted in a dramatic decrease in the energy of this high-energy hydration site, as shown by the WaterMap analysis combined with microsecond timescale molecular dynamics simulations. (S)-15 demonstrated both a favorable kinome selectivity profile and target engagement in a cellular environment and reduced GSK-3 autophosphorylation in neuronal SH-SY5Y cells. Overall, our findings highlight that even a slight adjustment in the location of a high-energy water can be decisive for ligand binding.

Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months to years. The clinical protocol of CKD forecasts that markers such as serum creatinine, the estimate of the glomerular filtration rate value, microalbuminuria, cystatin c are evaluated as routine markers. In recent years, new studies have identified new markers to diagnose and assess the level of kidney damage. The prevalence of CKD increases in subjects suffering from cardiovascular and metabolic diseases. The highest risk of cardiovascular risk in the CKD patient compared to the general population is related to risk factors such as hypertension, obesity, and specific renal disease factors such as albuminuria. Physical exercise, especially aerobic, has been seen through the analysis of urinary markers, able to mitigate the adverse effect of sedentary, hypertension and interstitial damage in patients with CKD and decrease the urinary levels liver-type fatty acid binding protein (L-FABP) and lower urinary albumin excretion.

Glycogen synthase kinase-3&beta, (GSK-3&beta, ) is a potential target in the field of Alzheimer&rsquo, s disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3&beta, inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure&ndash, activity relationships against GSK-3&beta, supported by 1 &micro, s molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties.