Computational Analysis of Physicochemical, Pharmacokinetic and Toxicological Properties of Deoxyhypusine Synthase Inhibitors with Antimalarial Activity

Malaria is a parasitic disease which has as etiological agents protozoa of the genus Plasmodium prevalent in tropical countries. The appearance of Plasmodium strains resistant to artemisinin has become necessary the development of new drugs using computational tools to combat this epidemic. Diverse transporter proteins can act as antimalarials targets, thereby being the enzyme deoxyhypusine synthase a promising antimalarial target. The present study aimed to investigate 15 most active inhibitors of deoxyhypusine synthase target, deposited in databases Binding DB, in order to trace a pattern of physicochemical, pharmacokinetic and toxicological properties of the inhibitors for this enzyme and propose new inhibitors of deoxyhypusine synthase target. The physicochemical properties were obtained according to the Lipinski parameters to evaluate oral absorption. Based on the certain properties were proposed three new inhibitors (A, B and C). The ADME/Tox properties were calculated for new inhibitors compared with results of the selected compounds. The fifteen inhibitors for oral administration showed satisfactory results, because they have adapted to the Lipinski parameters. In relation to the penetration of the blood-brain barrier the inhibitors analyzed showed penetration values less than 1, and ranged from 0.0411815 to 0.481764, being that the compound 1 showed value of CBrain/CBlood = 0.135467. Compound B showed a higher strength in plasma protein binding in relation to the compound 1, having a variation be-tween them of ±1.489344. Therefore, the compound B would present a longer halflife compared with compound 1. The proposed compounds showed positive and satisfactory results, being able to reach less adverse effects related to the central nervous system depending of administered dose.

Novel wine in an old bottle:Preventive and therapeutic potentials of andrographolide in atherosclerotic cardiovascular diseases

Atherosclerotic cardiovascular disease(ASCVD)frequently results in sudden death and poses a serious threat to public health worldwide.The drugs approved for the prevention and treatment of ASCVD are usually used in combination but are inefficient owing to their side effects and single therapeutic targets.Therefore,the use of natural products in developing drugs for the prevention and treatment of ASCVD has received great scholarly attention.Andrographolide(AG)is a diterpenoid lactone compound extracted from Andrographis paniculata.In addition to its use in conditions such as sore throat,AG can be used to prevent and treat ASCVD.It is different from drugs that are commonly used in the prevention and treatment of ASCVD and can not only treat obesity,diabetes,hyperlipidaemia and ASCVD but also inhibit the pathological process of atherosclerosis(AS)including lipid accumulation,inflammation,oxidative stress and cellular abnormalities by regulating various targets and pathways.However,the pharmacological mechanisms of AG underlying the prevention and treatment of ASCVD have not been corroborated,which may hinder its clinical development and application.Therefore,this review summarizes the physiological and pathological mechanisms underlying the development of ASCVD and the in vivo and in vitro pharmacological effects of AG on the relative risk factors of AS and ASCVD.The findings support the use of the old pharmacological compound(‘old bottle’)as a novel drug(‘novel wine’)for the prevention and treatment of ASCVD.Additionally,this review summarizes studies on the availability as well as pharmaceutical and pharmacokinetic properties of AG,aiming to provide more information regarding the clinical application and further research and development of AG.

Pharmacokinetic study about compatibility of Eucommia ulmoides and Psoralea corylifolia

Objective:The compatibility of Eucommia ulmoides(Eu)and Psoralea corylifolia(Pc)on the pharmacokinetic(PK)properties in the rat was explored in this study.Methods:Eu extract,Pc extract and the combined extracts(crude drug ratio was 2:1)was administered by gavage,respectively.Two PK experiments were conducted.In first one,the blood samples were collected via the occuli chorioideae vein to get the PK properties of the components.In second one,the blood samples were simultaneously collected via the internal jugular vein or portal vein at different time points and the concentrations of target ingredients were detected by LC/MS/MS to clear the location where the interaction of Eu and Pc took place in vivo.Results:Eight of 11 ingredients in Eu and Pc extract were determined in rat plasma.The exposure levels of geniposidic acid(GPA),aucubin(AU),geniposide(GP),pinoresinol diglucoside(PDG),psoralen glycosides(PLG)and isopsoralen glycosides(IPLG)were decreased 1/5–2/3 after administration of combined extracts.Comparing to the combined administration,the exposure of GPA and AU in plasma of single Eu administration collected via the portal vein were decreased 1/3–2/3,and the values of AUC0-24h and AUC0-∞ of GP collected from the portal vein or internal jugular vein were double increased.The other components’parameters were not significantly changed.Conclusion:In summary,the Pc and Eu combined administration could affect the exposure of the main components of Eu extract in rats due to the changed intestinal absorption.The research on the compatibility of Pc and Eu was helpful to guide the clinical administration of Eu and Pc simultaneously.