Quantum Chemical and Docking Insights into Bioavailability Enhancement of Curcumin by Piperine in Pepper

We combine quantum chemical and molecular docking techniques to provide new insights into how piperine molecule in various forms of pepper enhances bioavailability of a number of drugs including curcumin in turmeric for which it increases its bioavailability by a 20-fold. We have carried out docking studies of quantum chemically optimized piperine structure binding to curcumin, CYP3A4 in cytochrome P450, p-Glycoprotein and UDP-glucuronosyltransferase (UGT), the enzyme responsible for glucuronosylation, which increases the solubility of curcumin. All of these studies establish that piperine binds to multiple sites on the enzymes and also intercalates with curcumin forming a hydrogen bonded complex with curcumin. The conjugated network of double bonds and the presence of multiple charge centers of piperine offer optimal binding sites for piperine to bind to enzymes such as UDP-GDH, UGT, and CYP3A4. Piperine competes for curcumin’s intermolecular hydrogen bonding and its stacking propensity by hydrogen bonding with enolic proton of curcumin. This facilitates its metabolic transport, thereby increasing its bioavailability both through intercalation into curcumin layers through intermolecular hydrogen bonding, and by inhibiting enzymes that cause glucuronosylation of curcumin.本研究结合量子化学（quantum chemical）与分子对接（molecular docking）技术，针对多种胡椒制品中的胡椒碱（piperine）分子如何提升多种药物的生物利用度展开全新阐释，其中胡椒碱可使姜黄中姜黄素（curcumin）的生物利用度提升20倍。我们针对经量子化学优化后的胡椒碱结构，开展了其与姜黄素、细胞色素P450家族的CYP3A4、P-糖蛋白（p-Glycoprotein）以及负责葡萄糖醛酸化（glucuronosylation）反应、可提升姜黄素溶解度的尿苷二磷酸葡萄糖醛酸转移酶（UDP-glucuronosyltransferase, UGT）的分子对接研究。所有研究结果均证实，胡椒碱可结合于酶类的多个位点，同时可嵌入姜黄素分子，与姜黄素形成氢键复合物（hydrogen bonded complex）。胡椒碱所具备的共轭双键网络（conjugated network of double bonds）与多个电荷中心，为其与UDP-GDH、UGT及CYP3A4等酶类结合提供了最优位点。胡椒碱可通过与姜黄素的烯醇质子（enolic proton）形成氢键，竞争姜黄素的分子间氢键作用及其堆叠倾向。这一过程可促进姜黄素的代谢转运（metabolic transport），具体通过两种途径实现：一是借助分子间氢键嵌入姜黄素分子层，二是抑制介导姜黄素葡萄糖醛酸化的酶类，最终提升姜黄素的生物利用度。