Environmental and Cytotoxicity Risks of Graphene Family Nanomaterials
Suresh C. Pillai, Yvonne Lang in Toxicity of Nanomaterials, 2019
The π-π stacking interactions between aromatic residues and carbon-based NM largely dictate NM-protein interactions (Zuo et al., 2011). In fact, π-π stacking interactions are considered to dominate NM-protein interactions and modulate both adsorption kinetics and thermodynamics. Graphene’s unique sp2 hybridization exhibits in-plane σ bonds, the rigid backbone of the 2D atomic structure. In addition to π orbits perpendicular to the plane controlling inter-sheet interactions and as such are responsible for the aggregation of GFNs in physiological solutions. The GFN-related π bonding system impedes covalent interaction with environmental and biological systems but facilitates versatile reactions capable of forming complexes with organic compounds through π−π or H−π bonds (Balapanuru et al., 2010; Kim et al., 2011; Wu et al., 2011). The π-stacking interactions therefore encourage the random adsorption of biocomponents such as nucleic acids, proteins, enzymes, bacteria, and viruses on GFN surfaces (Hu and Zhou, 2013). For example, extensive nonspecific adsorption of serum albumin, proteins, and lectins on graphene-like surfaces have been widely recognized (Chen et al., 2011b; Haque et al., 2012; Salihoglu et al., 2012). π-Stacking interactions can also lead to a collapse of secondary and tertiary protein structures (Zuo et al., 2011). Consequently, these interactions between biomolecules and GFNs should not be overlooked (Pan et al., 2011). This nonspecific binding can produce competitive adsorption and trigger unexpected and/or adverse bio-responses.
Structure and function of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Venhorst et al. (2003) generated a homology model for CYP2D6 on the basis of crystallized rabbit CYP2C5 and is validated on its ability to reproduce binding orientations corresponding to metabolic profiles of the substrates. In docking studies with a series of substrates and inhibitors, this homology model accommodated codeine well, forming a hydrogen bond with Glu216, π-π stacking with Phe120, and van der Waals interaction with Phe483. For most ligands examined except sparteine, there is an interaction with either Glu216 or Asp301 (Venhorst et al. 2003). Debrisoquine, dextromethorphan, MAMC, and phenformin appeared to interact with both Glu216 and Asp301 for their basic nitrogen atoms. Phe120 is generally involved in the π-stacking with aromatic moieties of the ligands. Other residues including Ile106, Leu213, Ala305, Val308, Val370, Val374, and Phe483 are generally involved in hydrophobic interactions. Twenty-two active-site residues in SRS1-6 are identified in the CYP2D6 binding pockets, including those from SRS1 (Pro103, Pro105, Ile106, Phe112, Phe120, and Leu121), SRS2 (Leu213, Glu216, and Ser217), SRS3 (Phe243 and Gln244), SRS4 (Asp301, Ser304, Ala305, Val308, and Thr309), SRS5 (Ile369, Val370, Val374, and Thr375), and SRS6 (Phe483 and Leu484) (Venhorst et al. 2003). Respective mutation studies have confirmed the role of Glu216, Asp301, Ser304, Thr309, Phe120, and Phe383 in ligand binding and substrate metabolism.
Conjugation of Polymers with Biomolecules and Polymeric Vaccine Development Technologies
Mesut Karahan in Synthetic Peptide Vaccine Models, 2021
The mechanism and functional properties of biomacromolecules (protein, polysaccharide, etc.) formed by synthetic polyelectrolytes and water-soluble and insoluble complexes were investigated (Mustafaev et al. 1998). Water-soluble polymers have recently found a wide range of applications, both in theoretical polymer chemistry and practical application. In particular, the use of water-soluble systems as physiological active substances appears to be an immunological benefit (Nadakumar and Shakya 2012). Coordination and organometallic colloids and gels have attracted unique interest from scientists for application in new technologies within the production of biopolymers. Unfortunately, in step with the regarded strategies of guidance for these biomaterials, they are nonetheless quite basic and may be stated to be the result of coincidences instead of planning. In addition to coordination bonds in manufacturing, other non-covalent interactions, which include coordination colloids and gels, hydrogen bonds, stacking, and van der Waals forces, had been discovered and are recognized to work in collaboration. Because of the collective effect of these sensitive interactions, understanding and manipulating intermolecular connections are crucial to structural design and a number of properties in the molecules’ function. Therefore, fundamental studies that consist of innovation in chemistry, characterization strategies, and the improvement of effective strategies for shape-function assessment should be supported and expanded (Wang and McHale 2010).
The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
TaeHun Kim, Mohammad N. Morshed, Ashwini M. Londhe, Ji W. Lim, Ha E. Lee, Suengmok Cho, Sung J. Cho, Hayoung Hwang, Sang M. Lim, Jae Y. Lee, Jiyoun Lee, Ae N. Pae
In contrast, compound 44 (glide XP score= −11.20) fitted in reverse orientation inside the binding cavity (Figure 8(A)) which explains slightly lower binding affinity of 44 than 7. Because of the presence of a bulky phenylpiperazine group, the tricyclic core ring of compound 44 moved towards the space between intracellular loop1 residues such as Phe25, His46, and Leu49 interacting via strong pi stacked, pi-sulphur and pi-alkyl contacts respectively (Figure 8(C)). The phenylpiperazine side chain is pointed towards TM5 while interacts with Phe99 from TM3 via a strong pi-stacked interaction. The presence of pi-stacking interactions corroborates the superior activity observed from compounds with an aromatic ring compared to compounds with no aromatic side chains. Several pi-alkyl interactions with Val154, Leu150, Leu49, and Trp95 were also observed. The sulphur atom from the alkyl chain showed two pi-sulphur bonds with Trp53 and Trp95. The oxygen atom of the ethoxy group formed a hydrogen bond with Tyr57. Trp53 showed pi stacked and pi sigma contacts with the ethoxy phenyl ring as described in Figure 8(E).
Design and synthesis of novel rigid dibenzo[b,f]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mohammed Farrag El-Behairy, Walaa Hamada Abd-Allah, Mohamed M. Khalifa, Mohamed S. Nafie, Mohamed A. Saleh, Mohammed S. Abdel-Maksoud, Tarfah Al-Warhi, Wagdy M. Eldehna, Ahmed A. Al‐Karmalawy
Doxorubicin, as a reference standard, showed good binding interaction and bound some key amino acids and nucleobases of the target receptor revealing its potentiality as a topoisomerase II inhibitor and DNA intercalator16. The amino group of doxorubicin (at C4 of the pyran ring) showed the formation of an H-bond with DG10. Additionally, the carbonyl group linked to the tetracene nucleus at C9 of doxorubicin is bound to DC9 via an H-bond. Moreover, the oxygen atom and hydroxyl group linked to C7 and C6 of the tetracene nucleus, respectively, formed H-bond with DT9. Besides, the oxygen atom of the methoxy group linked to C4 of the tetracene nucleus of doxorubicin was involved in H-bonds with ARG503, which is a crucial amino acid. The aromatic ring formed pi–alkyl interaction with ARG503 and pi–pi interaction with the second aromatic ring. Furthermore, doxorubicin-induced van der Waal interactions with GLY478, LEU502, LYS456, ASP479, GLN778, ALA779, and MET782, Figure 9.
Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers
Published in Expert Opinion on Therapeutic Targets, 2019
Jarosław Przybycinski, Magdalena Nalewajska, Małgorzata Marchelek-Mysliwiec, Violetta Dziedziejko, Andrzej Pawlik
Small-molecule PAPR inhibitors elicit their effects by trapping the PARP enzyme within a region of DNA damage. This process stalls the replication fork and acts cytotoxically in neoplastic cells. Considering the key role of nicotinamide adenine dinucleotide (NAD+) in the catalytic domain activity of PARPs, the structures of PARPs generally resemble that of nicotinamide [10]. The common feature of PARPs is the presence of a benzamide pharmacophore [11]. Notably, a carboxamide group directly affects amino acids Gly202 and Ser242 of PARP enzymes. The presence of an aromatic ring enables pi-stacking interactions with aromatic amino acids [12]. PARP enzymes have different NAD+ binding pockets. The specificity depends on the affinity of the PARP inhibitor for other enzymes of this group. Some PARPs might also inhibit enzymes such as tankyrase 1 and 2, hexose-6-phosphate and inosine monophosphate dehydrogenases. There are significant differences regarding this issue across the entire group of drugs [11]. Introducing derivatives containing a quinazolinone ring allows the particles to interact not only with a NAD+ binding region but also with a region that binds adenine, which augments drug specificity. Veliparib and niraparib currently have the greatest specificities among the approved drugs [13]. Many PARP inhibitors contain a fluorine atom or atoms to increase their activities [14].
Related Knowledge Centers
- Aromaticity
- Benzene
- Chemistry
- DNA
- Molecular Orbital
- Nucleobase
- Protein Folding
- Rna
- Supramolecular Chemistry
- X-Ray Crystallography