Additionally, hydrophobic interactions with two aforementioned amino acid side chains occur. becomes progressively more susceptible to opportunistic infections. The late symptoms of the infection are referred to as acquired immunodeficiency syndrome (AIDS) [3]. The global epidemic has prompted virologists to understand the pathogenic processes caused by the virus, determine its structure, as well as search for preventive vaccines and antiviral drugs. Knowledge of the viral enzymes responsible for the replication of the virus (reverse transcriptase, protease, integrase) allows for synthesis and fast introduction of drugs, which are inhibitors of these active proteins, into therapy. Reverse transcriptase inhibitors prevent the HIV enzyme reverse transcriptase (RT) from converting single-stranded HIV RNA into double-stranded DNA. There are two types of RT inhibitors. Nucleoside/nucleotide RT inhibitors (NRTIs) are faulty DNA building blocks BAX that stop HIV DNA synthesis. Non-nucleoside RT inhibitors (NNRTIs) bind to RT, interfering with its ability to convert HIV RNA into HIV DNA. Nucleoside reverse transcriptase inhibitors are derivatives of 2,3-dideoxynucleosides. They are active only in the triphosphate form [4]. Human kinase-mediated phosphorylation occurs at the 5 position in three stages [5]. NRTIs are substrates for the enzyme and are incorporated into the DNA chain. Due to the lack of a hydroxyl group at the 3 position, formation of a phosphodiester bond with another nucleoside is impossible, and further elongation of the nucleic acid cannot occur, thereby inhibiting viral replication. Lamivudine and emtricitabine are Bakuchiol structurally remote from 2-deoxynucleosides. Instead of deoxyribose, they contain oxathiolane, which also prevents further elongation of the DNA. Fullerene is an allotrope of carbon. The fullerene molecules are composed of even number of carbon atoms that form a spherical polyhedron. C20 is the smallest possible fullerene. Bakuchiol It is composed of 12 pentagons and has a structure of a regular dodecahedron with a diameter of about 3.1 ?. The C20 molecule has 30 C-C bonds of about 1.46 ?. Next to C60, C20 has the most regular geometry of all fullerenes [6]. The latest research shows that fullerene derivatives could be novel, great antiviral compounds to treat the human immunodeficiency virus infection [7,8]. HIV protease and reverse transcriptase enzymes are the two targets for anti-HIV fullerene derivatives. Molecular modeling studies have demonstrated that C60 derivatives could act as HIV RT inhibitors [7,9,10]. In 2005, Mashino et al. [11] synthesized various malonic acid- and amino acid-type C60 derivatives and investigated the inhibitory activity of those compounds towards HIV RT. Machino continued his fullerene research, and in 2015, showed that pyridine/pyrimidine-type fullerene derivatives could inhibit the enzyme without cytotoxic effects [12]. The fullerene derivatives should therefore be considered new chemical entities with new biological activity as a result of overall structure rather than composition of two subcomponents. Here we performed in silico molecular modeling studies on compounds formed with C20 fullerene and lamivudine, zidovudine, and emtricitabine. Studied ligands were designed on the grounds of nucleoside reverse transcriptase inhibitors structures. The key difference in our studies is the replacement of dideoxyribose ring or oxathiolane with Bakuchiol a C20 fullerene. Three leading structures are proposed. They are built by pyrimidine or purine base and hydroxymethyl group attached in various positions to one side of C20. This is illustrated in Figure 1. The first type of substitution is based on the structure of most NRTIs, such as zidovudine. The second type is based on the structures of lamivudine and emtricitabine. Additionally, there is proposed also a third type of connection. Three bases were used: adenine, thymine, and cytosine. Additionally, non-substituted carbon atoms of the substituted fullerene rings were replaced with atoms of nitrogen, sulfur or boron. We also propose compounds with a methylene group connecting fullerene with the nitrogenous base. All the combinations used give 180 compounds in total. Replacement of one carbon atom in C20 with a nitrogen atom causes a loss of a double bond and addition of one hydrogen atom. In order to increase the comparability of the results, sulfur and boron derivatives as well as derivatives without heteroatoms have one double bond saturated, adding two hydrogen atoms. As a result, the fullerene core in every Bakuchiol designed compound has exactly 8 double bonds. Open in a separate window Figure 1 Substitution of C20 by purine or pyrimidine bases can occur in three ways. In order to increase the readability, hydrogen atoms and double bonds in the fullerene part were left out. (A) Substitution based.
