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.
The effects of Different Synthesis Methods and Catalysts on Crude Aspirin
Aspirin is one of the most used and well-known medicines world-wide. It can be synthesized by reacting acetic anhydride and salicylic acid in a warm temperature of around 60-80°C. This reaction is usually catalyzed by sulfuric or phosphoric acid. This paper will investigate alternative catalysts, safer and more environmentally friendly, as well as compare different synthesis methods with different heat mediums, one using a water bath and the other amicrowave. By doing so, the effects of the catalyst and the method of synthesis on the yield, purity and environmental consequence of crude aspirin synthesis will be deduced. The targeted utcome is to find the alternative method as more energy efficient, and to find a greener safer catalyst to sulfuric and phosphoric acid. Further background information, exploration, and explanation is in the appendix. The targeted outcome will be to find a viable alternative catalyst that is safer and more environmentally friendly, and to find that the microwave synthesis method consumes less energy.
Synthesize Sodium Sesquicarbonate and Increase Yield
In order to recycle disposable diapers, we investigated the conditions where sodium sesquicarbonate (Chemical formula Na2CO3・ NaHCO3・ 2H2O hereinafter called sesqui) precipitates selectively from sodium carbonate and the conditions for high yield. For the selective precipitation of sesqui, we defined the time required for the reaction solution to pass through the sesqui precipitation area in the Na2CO3-NaHCO3-H2O phase diagram (45°C) as Δ t. As a result, we revealed that Δt is involved in the selective precipitation of sesqui, and that we can synthesize sesqui without the expensive addition of L-Arginine as used in a previous research. Also, we proposed the “Stay method”, in which the supply of CO2 is stopped for 30 minutes to the lengthen the Δ t, and found that we could synthesize sesqui selectively even under conditions in which sodium bicarbonate is likely to be precipitated as well. Regarding the high yield of sesqui, the yield was greatly improved by the common ion effect of Na by adding NaOH to the reaction solution, sesqui synthesis by repeated reactions with CO2, and sesqui recovery by adding the anti-solvent ethanol, reaching a sesqui conversion rate of 95%. This means 109 g of sesqui can be synthesized from 100 g of Na2CO3. Moreover, we confirmed that these synthesized samples have almost the same detergency as commercial sesqui. We did a test calculation to reveal the usefulness of this research. First, if diaper recycling technology is put into practical use and all used diaper waste in Saijo City can be recycled, a reduction of 534 t/year of used diaper waste can be expected. This corresponds to a 2.3% reduction in Saijo City's waste output. From the ash that would ultimately remain after being recycled, we expect up to 35.3 t/year of synthesized sesqui using our experimental method. In addition, a CO2 reduction of 8.2 t/year is possible in the process, which is about equivalent to the volume of one gymnasium.
Synthesis of Substituted Pyrrolidin-2-ones and Isoindolines from Donor-Acceptor Cyclopropanes and Anilines/Benzylamines
The development of rapid and efficient synthetic approaches to the bioactive cyclic and polycyclic azaheterocycles is one of the most important challenges in organic synthesis. In this work effective and simple synthetic approaches to polysubstituted pyrrolidin-2-ones 2 and isoindolines 3 from donor-acceptor cyclopropanes 1, bearing the ester group as the one of acceptor substituents, and amines were developed. The γ- pyrrolidone based skeletons and isoindoline ring system is a constituent of many biologically active molecules, both natural and synthetic, and a key component of clinically relevant entities (Fig.1,2) [1,2]. The synthesis of pyrrolidin-2-ones 2 includes Lewis acid-catalyzed opening of the donor-acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide diversity of donor-acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents, can be involved in this transformation. In this process, donor-acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines as 1,1- dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives. The synthesis of the substituted isoindolines 3 is based on the domino-reaction between donor-acceptor cyclopropanes, bearing in ortho-position of aromatic substituent a bromomethyl group, and different primary amines (e.g., anilines, benzylamines, cycloalkylamines) was developed. The reaction involves the generation of secondary amine followed by nucleophilic ring opening of cyclopropane with amino group. Moreover, this process provided a new practical method for the rapid synthesis of benzo[b]pyrrolizidinone 4 from readily available starting materials.