Bisnaphthalimidopropyl Derivatives as Inhibitors of Leishmania SIR2 Related Protein 1

The NAD⁺‐dependent deacetylases, namely sirtuins, are involved in the regulation of a variety of biological processes such as gene silencing, DNA repair, longevity, metabolism, apoptosis, and development. An enzyme from the parasite Leishmania infantum that belongs to this family, LiSIR2RP1, is a NAD⁺‐dependent tubulin deacetylase and an ADP‐ribosyltransferase. This enzyme's involvement in L. infantum virulence and survival underscores its potential as a drug target. Our search for selective inhibitors of LiSIR2RP1 has led, for the first time, to the identification of the antiparasitic and anticancer bisnaphthalimidopropyl (BNIP) alkyl di‐ and triamines (IC₅₀ values in the single‐digit micromolar range for the most potent compounds). Structure–activity studies were conducted with 12 BNIP derivatives that differ in the length of the central alkyl chain, which links the two naphthalimidopropyl moieties. The most active and selective compound is the BNIP diaminononane (BNIPDanon), with IC₅₀ values of 5.7 and 97.4 μM against the parasite and human forms (SIRT1) of the enzyme, respectively. Furthermore, this compound is an NAD⁺‐competitive inhibitor that interacts differently with the parasite and human enzymes, as determined by docking analysis, which might explain its selectivity toward the parasitic enzyme.     

Theophylline: Old Drug in a New Light,Application in COVID-19 through Computational Studies

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.     

在涠洲12-1导管架设计中新技术新方法的应用

涠洲12-1导管架是一座8腿大型浅水导管架,位于南海西部北部湾,平均水深33.67m。风浪较大。针对此导管架在位分析和施工分析的特点,在设计中采用了新技术新方法,比较准确地模拟了结构的受力方式,解决了设计上的难题,优化了结构,节省了钢材,为今后的工程设计取得了经验。     

飞机中外对接件的结构疲劳寿命预测

为得到飞机中外对接件在载荷状态下的应力分布情况,合理的对其寿命进行估算,采用ANSYS软件对飞机中外对接件进行有限元分析并与试验值对比,得到应力分布情况,应用局部应力应变法做寿命的估算,其结果为结构细节改进和评价构件的疲劳分析提供依据。     

A Virtual Screening Method for Inhibitory Peptides of Angiotensin I–Converting Enzyme

Natural small peptides from foods have been proven to be efficient inhibitors of Angiotensin I–converting enzyme (ACE) for the regulation of blood pressure. The traditional ACE inhibitory peptides screening method is both time consuming and money costing, to the contrary, virtual screening method by computation can break these limitations. We establish a virtual screening method to obtain ACE inhibitory peptides with the help of Libdock module of Discovery Studio 3.5 software. A significant relationship between Libdock score and experimental IC₅₀ was found, Libdock score = 10.063 log(1/IC₅₀) + 68.08 (R² = 0.62). The credibility of the relationship was confirmed by testing the coincidence of the estimated log(1/IC₅₀) and measured log(1/IC₅₀) (IC₅₀ is 50% inhibitory concentration toward ACE, in μmol/L) of 5 synthetic ACE inhibitory peptides, which was virtual hydrolyzed and screened from a kind of seafood, Phascolosoma esculenta. Accordingly, Libdock method is a valid IC₅₀ estimation tool and virtual screening method for small ACE inhibitory peptides.     

Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies

β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer’s disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is −1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.     

关于Hill方程的一点思考

对近圆相对运动中Ｈｉｌｌ方程的精度进行了理论分析，指出Ｈｌｉｉ方程的发散性是由于没有计及非线性影响造成的。给出了Ｈｉｌｌ方程的改进形式，仿真表明，改进形式比经典Ｈｉｌｌ方程更符合实际情况。     

Responses to tail docking in calves and heifers

The primary objective of this study was to determine the behavioral and physiological effects of tail banding and atrophy using rubber rings 2 to 4 mo before first parturition in dairy heifers either with or without the use of epidural anesthesia. The secondary objective was to determine behavioral responses to tail banding using rubber rings in calves 7 to 42 d of age. Preparturient heifers (n = 24) were randomly assigned to one of four treatment groups: 1) tails were cleaned and handled; 2) tails were cleaned, handled, and an elastrator band was applied to the tail; 3) an epidural was administered 15 min before cleaning and handling; and 4) an epidural was administered 15 min before application of an elastrator band. Behavioral observations and physiological responses were collected for 6 wk. Additionally, behavioral responses to tail banding were recorded for 10 d on Holstein heifer calves that were 1 to 6 wk of age (n = 40). No significant differences in behavior were observed among treatment groups of preparturient heifers at any time during the 6-wk observation period. Preweaned calves that were 21 to 42 d of age demonstrated significantly more restlessness after application of tail bands compared to younger calves or control calves of the same age. Plasma cortisol values of preparturient heifers remained within limits previously described for nonstressed animals and no significant differences were detected among groups. Hematological values remained within the reference values for cattle, and there were no significant differences between groups except for relatively more eosinophils in the heifers that received epidurals. No significant differences in heart rate or body temperature were detected among groups.     

高性能计算在药物设计中的应用

计算机药物设计是高性能计算应用的一个重要领域。本文针对药物设计领域,简要介绍了高性能计算技术在蛋白质分子动力学模拟、药物虚拟筛选、药靶反向对接、个性化药物设计中的应用。