Exploring ligand binding pathways on proteins using hypersound-accelerated molecular dynamics

生体分子の動きを効率的に捉えるシミュレーション技術を開発 --超高周波超音波照射によってタンパク質と医薬品の結合計算を加速--. 京都大学プレスリリース. 2021-05-28.Capturing the dynamic processes of biomolecular systems in atomistic detail remains difficult despite recent experimental advances. Although molecular dynamics (MD) techniques enable atomic-level observations, simulations of “slow” biomolecular processes (with timescales longer than submilliseconds) are challenging because of current computer speed limitations. Therefore, we developed a method to accelerate MD simulations by high-frequency ultrasound perturbation. The binding events between the protein CDK2 and its small-molecule inhibitors were nearly undetectable in 100-ns conventional MD, but the method successfully accelerated their slow binding rates by up to 10–20 times. Hypersound-accelerated MD simulations revealed a variety of microscopic kinetic features of the inhibitors on the protein surface, such as the existence of different binding pathways to the active site. Moreover, the simulations allowed the estimation of the corresponding kinetic parameters and exploring other druggable pockets. This method can thus provide deeper insight into the microscopic interactions controlling biomolecular processes

Diagnosing metabolic acidosis in chronic kidney disease: importance of blood pH and serum anion gap

Metabolic acidosis is one of the most common complications of chronic kidney disease (CKD). It is associated with the progression of CKD, and many other functional impairments. Until recently, only serum bicarbonate levels have been used to evaluate acid-base changes in patients with reduced kidney function. However, recent emerging evidence suggests that nephrologists should reevaluate the clinical approach for diagnosing metabolic acidosis in patients with CKD based on two perspectives; pH and anion gap. Biochemistry and physiology textbooks clearly indicate that blood pH is the most important acid-base parameter for cellular function. Therefore, it is important to determine if the prognostic impact of hypobicarbonatemia varies according to pH level. A recent cohort study of CKD patients showed that venous pH modified the association between a low bicarbonate level and the progression of CKD. Furthermore, acidosis with a high anion gap has recently been recognized as an important prognostic factor, because veverimer, a nonabsorbable hydrochloride-binding polymer, has been shown to improve kidney function and decrease the anion gap. Acidosis with high anion gap frequently develops in later stages of CKD. Therefore, the anion gap is a time-varying factor and renal function (estimated glomerular filtration rate) is a time-dependent confounder for the anion gap and renal outcomes. Recent analyses using marginal structural models showed that acidosis with a high anion gap was associated with a high risk of CKD. Based on these observations, reconsideration of the clinical approach to diagnosing and treating metabolic acidosis in CKD may be warranted

Total Replacement of Fish Meal by the Combination of Fish Residue Meal and Soy Protein from Soymilk in the Diet of Red Sea Bream (<i>Pagrus major</i>)

Three experiments were performed to explore (i) the complete replacement of fish meal (FM) with a combination of fish residue meal (FRM, 65% round discarded fish + 35% byproduct), soy protein concentrate (SPC) from soymilk and corn gluten meal (CGM) in Trial 1 and (ii) the utilization of diets composed of increasing byproducts in FRM in the summer (Trial 2) and winter (Trial 3) seasons. In Trial 1, the ratio of (SPC + CGM):FM in the control diet (C) was 8:2. The FM component from diet C was replaced with FRM (diet, RM20), where the ratio of (SPC + CGM):FRM became 8:2, and this ratio was changed to 6:4, 4:6 and 2:8, and referred to as RM40, RM60 and RM80, respectively. In Trials 2 and 3, the ratios of round discarded fish and byproducts in FRM were adjusted to 65:35 (FRM1), 30:70 (FRM2) and 0:100 (FRM3), and the FRM component from diet RM40 in Trial 1 was replaced with FRM1, FRM2 and FRM3 to formulate diets RM1, RM2 and RM3, respectively. In Trials 1, 2 and 3, rearing periods were 10, 8 and 12 weeks, respectively. In Trials 1 and 3, there were no significant differences in growth parameters, nutrient retention efficiency or plasma constituents among the treatments, irrespective of the inclusion levels of FRM in the diets (p > 0.05). Although there were no significant differences in final mean weight (p > 0.05), daily feeding rate and feed conversion ratio in diet RM3 were significantly higher and lower, respectively, compared to the control group in Trial 2 (p < 0.05). These results suggest that FM can be entirely replaced with FRM, and that the total elimination of round discarded fish from FRM does not affect growth or health status in red sea bream either in summer or winter seasons

Structure-Based De Novo Molecular Generator Combined with Artificial Intelligence and Docking Simulations

Recently, molecular generation models based on deep learning have attracted significant attention in drug discovery. However, most existing molecular generation models have a serious limitation in the context of drug design wherein they do not sufficiently consider the effect of the three-dimensional (3D) structure of the target protein in the generation process. In this study, we developed a new deep learning-based molecular generator, SBMolGen, that integrates a recurrent neural network, a Monte Carlo tree search, and docking simulations. The results of an evaluation using four target proteins (two kinases and two G protein-coupled receptors) showed that the generated molecules had a better binding affinity score (docking score) than the known active compounds, and they possessed a broader chemical space distribution. SBMolGen not only generates novel binding active molecules but also presents 3D docking poses with target proteins, which will be useful in subsequent drug design

Association between urinary uric acid excretion and kidney outcome in patients with CKD

Abstract Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15–60 mL/min/1.73 m2. The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13–2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney