Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2).
Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2).
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DOI：
10.1186/s12906-018-2116-x
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发表时间：
2018-02-02
影响因子：
--
通讯作者：
Rashid MA
中科院分区：
文献类型：
--
作者：
Khan MF;Nahar N;Rashid RB;Chowdhury A;Rashid MA
桦木酸（Betulinic acid，BA）是一种天然三萜类化合物，具有广泛的生物和药用活性，包括抗炎活性。因此，进行该理论研究以评价（a）物理化学性质，例如酸解离常数（pKa）、分配系数（logD）、分配系数（logP）、水溶解度（logS）、溶剂化自由能、偶极矩、极化率、超极化率和不同的反应性描述符，（B）药代动力学性质，例如人肠吸收（HIA）、细胞渗透性，皮肤渗透性（PSkin）、血浆蛋白结合（PPB）、血脑屏障（BBB）渗透，（c）毒理学特性，包括致突变性、致癌性、hERG基因抑制风险和（d）抗炎作用的分子机制，这将有助于分析方法的开发和BA衍生物的合成。使用MarvinSketch 15.6.29和Gaussian 09软件包计算物理化学性质。在在线服务器PreADMET上计算药代动力学和毒理学性质。此外，在PyRx 0.8中的AutoDock上进行分子对接研究。由于BA的电离导致分配系数的降低，水溶解度随着pH的增加而增加。在水、二甲基亚砜、乙腈、正辛醇、氯仿和四氯化碳中的溶剂化能分别为− 41.74 kJ/mol、− 53.80 kJ/mol、− 66.27 kJ/mol、− 69.64 kJ/mol、− 65.96 kJ/mol和− 60.13 kJ/mol。从极化率和柔软度的结果，很明显，BA是不太稳定的，因此，在水中的动力学反应性更强。BA表现出良好的人体肠道吸收（HIA）和中等的细胞渗透性。此外，由于通过BBB的高渗透性，BA也表现出阳性CNS活性。毒理学研究表明，BA对小鼠无致癌性，但有致突变性。BA与PLA 2的分子对接研究表明，BA与GLY 22和GLY 29通过氢键相互作用，与LEU 2、PHE 5、HIS 6、ALA 17、ALA 18、HIS 47和TYR 51通过不同类型的疏水相互作用。BA的结合亲和力为− 41.00 kJ/mol，与强效抑制剂6-苯基-4（R）-（7-苯基-庚酰氨基）-己酸（BR 4）的结合亲和力（− 33.89 kJ/mol）相当。我们计算的性质可能有助于分析方法的发展，以测定BA或开发BA衍生物具有更好的药代动力学和毒理学特征。
Betulinic acid (BA) is a natural triterpenoid compound and exhibits a wide range of biological and medicinal properties including anti-inflammatory activity. Therefore, this theoretical investigation is performed to evaluate (a) physicochemical properties such as acid dissociation constant (pKa), distribution coefficient (logD), partition coefficient (logP), aqueous solubility (logS), solvation free energy, dipole moment, polarizability, hyperpolarizability and different reactivity descriptors, (b) pharmacokinetic properties like human intestinal absorption (HIA), cellular permeability, skin permeability (PSkin), plasma protein binding (PPB), penetration of the blood brain barrier (BBB), (c) toxicological properties including mutagenicity, carcinogenicity, risk of inhibition of hERG gene and (d) molecular mechanism of anti-inflammatory action which will aid the development of analytical method and the synthesis of BA derivatives. The physicochemical properties were calculated using MarvinSketch 15.6.29 and Gaussian 09 software package. The pharmacokinetic and toxicological properties were calculated on online server PreADMET. Further, the molecular docking study was conducted on AutoDock vina in PyRx 0.8. The aqueous solubility increased with increasing pH due to the ionization of BA leading to decrease in distribution coefficient. The solvation energies in water, dimethyl sulfoxide (DMSO), acetonitrile, n-octanol, chloroform and carbon tetrachloride were − 41.74 kJ/mol, − 53.80 kJ/mol, − 66.27 kJ/mol, − 69.64 kJ/mol, − 65.96 kJ/mol and − 60.13 kJ/mol, respectively. From the results of polarizability and softness, it was clear that BA is less stable and hence, kinetically more reactive in water. BA demonstrated good human intestinal absorption (HIA) and moderate cellular permeability. Further, BA also exhibited positive CNS activity due to high permeability through BBB. The toxicological study revealed that BA was a mutagenic compound but noncarcinogenic in mice model. Moreover, molecular docking study of BA with PLA2 revealed that BA interacts with GLY22 & GLY29 through hydrogen bond formation and LEU2, PHE5, HIS6, ALA17, ALA18, HIS47 and TYR51 through different types of hydrophobic interactions. The binding affinity of BA was − 41.00 kJ/mol which is comparable to the binding affinity of potent inhibitor 6-Phenyl-4(R)-(7-Phenyl-heptanoylamino)-hexanoic acid (BR4) (− 33.89 kJ/mol). Our computed properties may assist the development of analytical method to assay BA or to develop BA derivatives with better pharmacokinetic and toxicological profile.
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分离β酸，其甲基酯和瓜伊安娜倍半萜与蛋白酪氨酸磷酸酶1B抑制活性，来自Saussurea Lappa C.B. Clarke的根。
DOI：
10.3390/molecules14010266
发表时间：
2009-01-08
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Choi JY;Na M;Hyun Hwang I;Ho Lee S;Young Bae E;Yeon Kim B;Seog Ahn J
通讯作者：
Seog Ahn J
影响因子：
--
作者：
Carvalho BM;Santos JD;Xavier BM;Almeida JR;Resende LM;Martins W;Marcussi S;Marangoni S;Stábeli RG;Calderon LA;Soares AM;Da Silva SL;Marchi-Salvador DP
通讯作者：
Marchi-Salvador DP
影响因子：
3.8
作者：
Cabrera, MA;González, I;Bermejo, M
通讯作者：
Bermejo, M
影响因子：
15
作者：
Bach, RD;Ayala, PY;Schlegel, HB
通讯作者：
Schlegel, HB
影响因子：
6.3
作者：
CORNFORD, EM;PARDRIDGE, WM;OLDENDORF, WH
通讯作者：
OLDENDORF, WH