In Silico Modeling of Lovastatin Analogues as Inhibitors of HIV-1 Nef Protein
Currently, no method can completely eliminate the human immunodeficiency virus (HIV) in an infected person. HIV employs an accessory protein called Nef that forms a complex with cellular AP-1, preventing detection of HIV-infected cells. Lovastatin has been recently identified to inhibit the formation of said Nef-AP-1 complex, but its effective concentration is remarked to be far higher than other Nef inhibitors. This study aims to develop a modified lovastatin molecule exhibiting higher binding affinity to the HIV-1 Nef protein than lovastatin in silico. Modified lovastatin molecules based on the interaction map of lovastatin with Nef were modeled, and flexible ligand-flexible receptor docking to the Nef binding site was performed using AutoDock Vina. Residues within the Nef binding site identified by Liu et al. (2019) to be crucial (Glu-63, Val-66, Phe-68, Asp-108, Leu-112, Tyr-115) were set as flexible. Fragment-based drug design was utilized to append molecular fragments to lovastatin in order to maximize its interactions with said crucial residues. From the fragment-based approach, molecule F4 ((1S,3S)‐8‐{2‐[(2R,4R)‐4‐chloro‐6‐oxooxan‐2‐yl]ethyl}‐3‐(hydroxymethyl)‐7‐methyl‐1,2,3,4‐tetrahydronaphthalen‐1‐yl 4‐aminobenzoate) exhibited a binding affinity of -9.0 kcal/mole, and its estimated IC50 ranges between 0.25-0.51 μM which is at least 7.5 times lower than the reported IC50 of lovastatin from literature. This study presents insights on the key modifications to improve lovastatin as an HIV-1 Nef inhibitor and pertinent information about the Nef binding site for future drug development studies.
In Silico Modeling of Lovastatin Analogues as Inhibitors of HIV-1 Nef Protein
Currently, no method can completely eliminate the human immunodeficiency virus (HIV) in an infected person. HIV employs an accessory protein called Nef that forms a complex with cellular AP-1, preventing detection of HIV-infected cells. Lovastatin has been recently identified to inhibit the formation of said Nef-AP-1 complex, but its effective concentration is remarked to be far higher than other Nef inhibitors. This study aims to develop a modified lovastatin molecule exhibiting higher binding affinity to the HIV-1 Nef protein than lovastatin in silico. Modified lovastatin molecules based on the interaction map of lovastatin with Nef were modeled, and flexible ligand-flexible receptor docking to the Nef binding site was performed using AutoDock Vina. Residues within the Nef binding site identified by Liu et al. (2019) to be crucial (Glu-63, Val-66, Phe-68, Asp-108, Leu-112, Tyr-115) were set as flexible. Fragment-based drug design was utilized to append molecular fragments to lovastatin in order to maximize its interactions with said crucial residues. From the fragment-based approach, molecule F4 ((1S,3S)‐8‐{2‐[(2R,4R)‐4‐chloro‐6‐oxooxan‐2‐yl]ethyl}‐3‐(hydroxymethyl)‐7‐methyl‐1,2,3,4‐tetrahydronaphthalen‐1‐yl 4‐aminobenzoate) exhibited a binding affinity of -9.0 kcal/mole, and its estimated IC50 ranges between 0.25-0.51 μM which is at least 7.5 times lower than the reported IC50 of lovastatin from literature. This study presents insights on the key modifications to improve lovastatin as an HIV-1 Nef inhibitor and pertinent information about the Nef binding site for future drug development studies.
透過相轉移催化劑合成Chromeno[4,3-b]pyrrolidine之衍生物
本研究之反應產物Chromeno[4,3-b]pyrrolidine之衍生物含有吡咯烷及二氫苯并哌喃的骨架，而此二者存在於許多藥物及天然物中，例如：尼古丁及蛋白質中的脯胺酸皆為吡咯烷的衍生物，含有二氫苯并哌喃骨架的藥物則通常被應用於消炎藥物中。本研究主要反應是以對甲基苯醌衍生物與亞胺葉立德前驅物在相轉移催化劑及無機鹼的催化下進行(3+2)環加成反應與oxa-1,6-加成反應，合成出Chromeno[4,3-b]pyrrolidine之衍生物。利用改變不同的相轉移催化劑、溶劑和無機鹼的種類及各反應物的當量數，篩選出進行本反應的最佳反應條件。在此優化條件下，進一步使用不同的掌性相轉移催化劑，以探討本反應之光學活性。並利用無機鹼的篩選，以排除背景反應發生的可能性。希望最後能於起始物上替換不同種類的取代基，以探討本反應之反應活性，並增加其未來應用的多樣性。