CONTEXT:Graphene is considered to be a wonder material with widespread applications. However, its potential for recovering methylated DNA bases has not yet been explored. DNA methylation is implicated in the development of several health issues such as mutation, ageing, cancer and neurodegenerative diseases. The cytotoxic N7-methylated guanine (N7mG) is the most abundantly occurring methylated DNA lesion. Therefore, we have theoretically investigated the reactions of pristine, heteroatom-doped and functionalized graphene with N7mG cation with an intention to understand the efficacy of graphene in repairing this lesion. The epoxide- and thioepoxide-functionalized graphene can effectively restore guanine from the N7mG cation in both gas and aqueous phases. Pristine and BN-codoped graphene are, however, found to be unsuitable for this work. Thus, the present study offers valuable insights into how graphene may help in repairing N7mG and other modified DNA bases. METHODS:The calculations related to energetics, structural optimizations, natural bond orbitals (NBOs) and DOS were performed using two functionals (M06-2X and wB97X-D) of density functional theory (DFT) in association with 6-31G* and 6-31+G** basis sets, as available in the Gaussian 09 quantum chemistry code. The IEF-PCM was used for the aqueous phase calculations. The CHelpG charges were used for charge transfer analysis.

To understand the scavenging action of chlorophyll found in most of the vegetables towards hydroxyl (OH•) radicals, its reactions with hydroxyl (OH•) radicals via RAF, HAT and SET mechanisms have been investigated theoretically using two layer ONIOM [M06-2X/6-31G(d) (High):M06-2X/3-21G (Low)] method and M06-2X/6-311 + G(d,p) level of density functional theory.It is found that RAF and HAT reactions are exergonic in both gaseous and aqueous media whereas SET reactions are endergonic in both media. However, all the RAF, HAT and SET reactions studied here are found to be more favourable in aqueous media vs. gas phase. This study concludes that chlorophyll can efficiently scavenge OH• radicals preferably via RAF and HAT mechanisms and intake of water with chlorophyll can enhance its scavenging actions.

Recently, a few antiviral drugs viz Molnupiravir (EIDD-1931), Favipiravir, Ribavirin, Sofosbuvir, Galidesivir, and Remdesivir are shown to be beneficial against COVID-19 disease. These drugs bind to the viral RNA single strand to inhibit the virus genome replication. Similarly, recently, some artificial nucleotides, such as P, J, B, X, Z, V, S, and K were proposed to behave as potent antiviral candidates. However, their activity in the presence of the most reactive hydroxyl (OH) radical is not yet known. Here, the possibility of RNA strand break due to the OH radical-induced C1′-hydrogen (H) abstraction reaction of the above molecules (except Remdesivir) is studied in detail by considering their nucleotide conformation. The results are compared with those of the natural RNA nucleotides (G, C, A, and U). Due to low Gibbs barrier-free energy and high exothermicity, all these nucleotides (except Remdesivir) are prone to OH radical-induced C1′-H abstraction reaction. As Remdesivir contains a C1′-CN bond, the OH radical substitution reactions at the CN and C1′ sites would likely liberate the catalytically important CN group, thereby downgrading its activity. Initially, the B3LYP-D3 dispersion-corrected density functional theory method and 6–31 + G* basis set were used to optimize all reactant, transition state, and product complexes in the implicit aqueous medium. Subsequently, the structures of these complexes were further optimized by using the ωB97X-D dispersion-corrected density functional theory method and cc-PVTZ basis set in the aqueous medium. The IEFPCM method was used to model the aqueous medium.

The sulfane sulfur molecules are known to regulate many biological processes for the normal functioning of cells. Herein, the interactions of pristine, B-doped, N-doped, BN-codoped, monovacancy defected, and Stone-Wales (SW) defected graphene with HSSS & sdot; radical have been investigated theoretically in the framework of density functional theory (DFT) with an aim to understand if pristine or modified graphene can be used as an adsorbent for HSSS & sdot; radical. The analysis based on the structural details, Wiberg bond, ZPE-corrected adsorption energies, reaction enthalpies, reaction free energies and density of states (DOS) reveal that the pristine, BN-codoped, monovacancy defected and SW defected graphene would serve as potential adsorbents for adsorption of HSSS & sdot; radicals; the monovacancy defected graphene could be the best choice for this job. It is found that the B-doped graphene would act as a weak adsorbent but the N-doped graphene would not at all be suitable for adsorption of HSSS & sdot; radicals.

The functionality of a semisynthetic DNA in the biological environment will depend on the base pair nature of its complementary base pairs. To understand this, base pair interactions between complementary bases of recently proposed eight second-generation artificial nucleobases are studied herein by considering their rare tautomeric conformations and a dispersion-corrected density functional theoretic method. It is found that the binding energies of two hydrogen-bonded complementary base pairs are more negative than those of the three hydrogen-bonded base pairs. However, as the former base pairs are endothermic, the semisynthetic duplex DNA would involve the latter base pairs.

Herein, we aim to explore the efficiency of graphene in scavenging the carcinogenic methane diazonium ions (CH3N2+) which are capable of methylating DNA and other biomolecules readily. Therefore, methylation of graphene (pristine and S-doped) by CH3N2+ was investigated theoretically using density functional theory. Our calculations show that graphene (both pristine and S-doped) can be readily methylated by CH3N2+. However, as S-doped graphene exhibited better reactivity than pristine graphene, we believe that the former would act as a better scavenger for CH3N2+ than the latter one.

The curcumin is a well-known antioxidant that can scavenge free radicals efficiently. The methyl free radicals, generated by the metabolism of various genotoxic compounds such as hydrazines and peroxides, can methylate various sites in DNA. Herein, we have carried out density functional theory calculations to investigate the scavenging activity of curcumin toward the methyl and ethyl radicals through radical adduct formation (RAF), hydrogen atom transfer (HAT) and single electron transfer (SET) mechanisms. The SET mechanism is found to be highly endergonic and so not viable. Our calculations show that the curcumin can scavenge methyl radicals through both RAF and HAT mechanisms but RAF would be preferred over the HAT. Further, it is found that the curcumin can scavenge methyl radicals more efficiently as compared to ethyl radicals through RAF mechanism.

It is known that methylating agents methylate DNA by transferring a methyl cation (CH3+) to the nucleophilic sites in DNA bases and DNA methylation is implicated in cancer and other pathological conditions. Therefore, it is important to scavenge CH3+ ion in order to protect DNA from methylation. Graphene is considered to be a versatile material for use in a wide variety of fields including sensors, antioxidants, drug delivery and DNA sequencing. In this work, we have theoretically investigated the interaction of CH3+ ions with graphene surface with an aim to understand if pristine graphene can be used as a substrate to adsorb CH3+ cations generated from harmful methylating agents. The computed adsorption energies show that adsorption of one, two and three CH3+ ions on graphene is favourable as the adducts thus formed are found to be substantially stable in both gas phase and aqueous media. The Bader charge transfer analysis and density of states (DOS) calculation also indicate a strong interaction between graphene and CH3+ ions. Thus, our results show that pristine graphene can be used as a substrate to scavenge CH3+ ions. The spin polarised density functional theory (DFT) calculations employing PBE functional, ultrasoft pseudopotentials and plane wave basis set having kinetic energy cut-offs of 40 Ry and 400 Ry, respectively, for wave functions and charge densities were carried out to study the adsorption of CH3+ ion(s) on the pristine graphene surface. The Grimme’s DFT-D2 method was used for the estimation of van der Waals interactions. The ‘dipole correction’ along z-direction was also applied for adsorption study. The Marzari–Vanderbilt smearing and Monkhorst–Pack k-point grid were employed for the Brillouin zone sampling. A 6 × 6 graphene supercell with a vertical cell dimension of 18 Å was considered for the adsorption study. The charge transfer between the CH3+ ion(s) and graphene was estimated using Bader charge analysis. The implicit solvation model (SCCS) was used to estimate the solvent effect of aqueous media. All the calculations were performed using QUANTUM ESPRESSO package.

In this research, we have reported the synthesis of Methyl-4-(4-chlorophenyl)-5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate which is a hybrid of two different biologically active structures. The obtained product was characterized by FT-IR, 1HNMR, 13C NMR, SCXRD and HR-MS. The obtained compound was recrystallized in ethanol giving colourless pure single crystals. SCXRD analysis showed two symmetry inde-pendent asymmetric molecules with interesting structural features. Multiple graph sets were also observed which supported the formation of a supramolecular network. DFT studies using B3LYP and M06-2X functions revealed two stable conformers which is in support of the crystal structures obtained. Furthermore, in silico molecular docking analysis in Eg5 kinesin and survivin protein revealed binding affinities of-6.9 kcal/mol and-6.1 kcal/ mol respectively. All the results obtained suggests the need of further exploration to discover the complete pharmaceutical potential.

A triple helical DNA can control gene expression, help in homologous recombination, induce mutations to facilitate DNA repair mechanisms, suppress oncogene formations, etc. However, the structure and function of semisynthetic triple helical DNA are not known. To understand this, various triplets formed between eight artificial nucleobases (P, Z, J, V, B, S, X, and K) and four natural DNA bases (G, C, A, and T) are studied herein by employing a reliable density functional theoretic (DFT) method. Initially, the triple helix-forming artificial nucleobases interacted with the duplex DNA containing GC and AT base pairs, and subsequently, triple helix-forming natural bases (G and C) interacted with artificial duplex DNA containing PZ, JV, BS, and XK base pairs. Among the different triplets formed in the first category, the C-JV triplet is found to be the most stable with a binding energy of about − 31 kcal/mol. Similarly, among the second category of triplets, the Z-GC and V-GC triplets are the most stable. Interestingly, Z-GC and V-GC are found to be isoenergetic with a binding energy of about − 30 kcal/mol. The C-JV, and Z-GC or V-GC triplets are about 12–14 kcal/mol more stable than the JV and GC base pairs respectively. Microsolvation of these triplets in 5 explicit water molecules further enhanced their stability by 16–21 kcal/mol. These results along with the consecutive stacking of the C-JV triplet (C-JV/C-JV) data indicate that the synthetic nucleobases can form stable semisynthetic triple helical DNA. However, consideration of a full-length DNA containing one or more semisynthetic bases or base pairs is necessary to understand the formation of semisynthetic DNA in living cells.

It is reported that NAMI-A and other Ru-anticancer complexes preferably bind with the N7 site of guanine and can also form DNA inter-strand cross-links. Therefore, in order to understand the DNA cross-link formation capability of NAMI-A, we have investigated here the structure and energetics of the reactions of the GN7-NAMI-A (a monofunctional adduct of NAMI-A with the N7 site of guanine) with the N3, N7, and O6 sites of guanine; the N1, N3, and N7 sites of adenine; the O2 and N3 sites of cytosine; and the O2 and O4 sites of thymine, using the M06-2X functional of density functional theory. It is found that the GN7-NAMI-A can form stable cross-linked products at all the sites studied here except at the N3 site of cytosine and O2 site of thymine. The calculated reaction free energies and reaction enthalpies indicate that the N3 site of adenine (AN3) and N7 site of guanine (GN7) are most exothermic among all the studied reactions. This study shows that NAMI-A would favorably form the cross-linked products involving the N7 site of guanine at one side and the N7 site of guanine or the N3 site of adenine at the other side.

The osmium (Os)-based complexes have recently attracted significant attention as a potential anticancer drug due to their diverse cytotoxic activities and other remarkable properties. However, the mechanisms of action of these complexes are not properly understood. Herein, the density functional theory calculations have been carried out to investigate the first hydrolysis reactions of Os-KP418, an analogue of the Ru(III)-based anticancer drug KP418, and the reactions of Os-KP418 and its aquated product [Os-KP418 (aqua)] at the N7 site of guanine to explore the mechanisms of action of Os-KP418. It is found that the Os-KP418 is first hydrolyzed via substitution of a chloride ligand by a water molecule to produce a more reactive aquated species [Os-KP418 (aqua)] which then react with the N7 site of guanine.

Hydroxyl radical (OH radical) is the most harmful free radical amongst the Reactive Oxygen Species (ROS) responsible for numerous diseases of DNA damage like mutagenesis, carcinogenesis and ageing. Therefore, it is important to find a suitable scavenger for OH radical. In the present contribution, we aim to investigate the ability of pristine armchair-SWCNT and B/N/P-doped armchair-SWCNT to scavenge OH radicals using DFT calculations. The calculations reveal that the B/P-doped armchair-SWCNTs can act as a better scavenger for OH radical compared to pristine armchair-SWCNT but N-doped armchair-SWCNT does not act as a better scavenger for OH radical compared to pristine armchair-SWCNT. Furthermore, the developed scavenger is examined in terms of large-scale availability, biocompatibility, conductivity, stability and reactivity. For both in vivo and in vitro studies, the work is found to useful for enhancing SWCNT as a free radical scavenger.

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs.

In this study, a novel pyridone-based phthalimide fleximer, that is, ethyl 5-cyano-6-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-4-(3-methoxyphenyl)-2-methylnicotinate, was synthesized, and its structure was established by the single-crystal X-ray diffraction method. The supramolecular self-assembly of the titled compound through noncovalent interactions was then investigated thoroughly. The titled compound crystallized with two symmetry-independent molecules (A and B, Z' = 2). In agreement with experimental observations, our density functional theory calculations also showed that the titled compound has a flexible motif and can occur in various conformations, including molecules A and B. The investigation of the supramolecular framework revealed that the molecules are notably bound by the nonclassical C-H···O and C-H···N hydrogen bonds and C-H···π interactions. Hirshfeld surface analysis was carried out to quantify the various intermolecular interactions. The dual anti-inflammatory activity of the tilted compound was also explored by molecular docking in the active sites of 5-LOX and COX-2 receptors, which revealed good binding affinities of -9.0 and -8.6 kcal/mol, respectively.

In this study, for the first time, we have used Citrus macroptera juice to synthesize dihydropyrimidine (DHPM) derivatives via the Biginelli reaction, which showed better yield, shorter reaction time, and did not require an organic solvent for the reaction. A series of DHPM derivatives were synthesized, and characterized, and structural analysis was achieved through SCXRD & Hirshfeld surface analysis. We observed that these synthesized dihydropyrimidine (DHPM) derivatives showed C-H⋯π, C-H⋯O, C-H⋯N, C-H⋯C, lone pair⋯π, π⋯π, etc. interactions. We also performed in silico studies for their inhibitory activities against human kinesin Eg5 enzyme, and the cytotoxic activity of the synthesized compounds was carried out against A549 lung adenocarcinoma cells. In silico analysis demonstrated that compounds with a chloro-group at the 3- or 4-position in the substituted ring of DHPM showed higher binding affinity for the human kinesin Eg5 enzyme (-7.9 kcal mol-1) than the standard drug monastrol (-7.8 kcal mol-1). Furthermore, in vitro cellular studies revealed that compounds with a chloro-group at the 3- or 4-position in the substituted ring of DHPM induced significant cell death in human A549 lung adenocarcinoma cells. This result indicates that a deactivating group (chlorine) at the 3- or 4-position in the substituted ring of DHPM might be a promising anticancer drug candidate for treating different types of cancers, particularly cancer of the lung.

In this paper, we aim to determine whether the N7-methylation can influence the base pairing properties of guanine by promoting the formation of guanine enol-tautomers. The keto- to -enol-tautomerization of N7-methylguanine (N7mG) and its base pairing patterns with all the canonical DNA bases have been investigated at the M06-2X/6-311+G(d,p) level of density functional theory. The barrier free energy calculations reveal that N7-methylation does not promote the keto- to enol- tautomerization of guanine. The Watson-Crick-like enol-N7mG:T1 or enol-N7mG:T2 base pair similar to what is observed experimentally is found to be energetically more stable than the keto-N7mG:T base pairs. However, the keto-N7mG:C1 which is structurally similar to the canonical G:C base pair is the most stable base pair among all the base pairs studied here. Thus, our calculations predict that N7mG would pair preferably with cytosine during DNA replication but there is also a probability that it can cause mutation through mispairing with thymine, in agreement with experimental observations.

It is believed that HOOO. radicals play a key role in atmospheric and environmental chemistry as well as in biological oxidation reactions. In the present contribution, we aim to understand the ability of graphene to scavenge HOOO. radicals by studying the adsorption of HOOO. radical on the pristine and doped (B-doped, N-doped and (B,N)-codoped) graphene using density functional theory (DFT) calculations. It is found that mechanisms of adsorption of HOOO. radical on the pristine and N-doped graphene involve physisorption whereas those on the B-doped and (B,N)-codoped graphene involve chemisorption. The interaction between the pristine graphene and HOOO. radical is found to be weaker than that between doped graphene and HOOO. radical. Our calculations demonstrate that both the pristine and doped-graphene studied here can scavenge the HOOO. radicals. However, the B- and N-doped graphene can do this job more effectively.

This article compares a reported hydrophobic and photobiologically inert porphyrin synthon, (NPh)TPyP, bearing a single meso-4-nitrophenyl group and three meso-pyridyl groups (A3B type) with a new photobiologically active metal-free porphyrin, P3N, and its zinc-complex, P3NZn, which bear a meso-4-nitrophenyl group along with three distal pyridyl groups. Both P3N and P3NZn experience ruptured π-conjugation with the porphyrin macrocycle and attain hydrophilicity, as indicated via density functional theory (DFT) calculations, becoming photobiologically active under in vitro conditions. The non-invasive photodynamic activity (PDA) predominantly shown by the zinc-complex P3NZn (with higher hydrophilicity) towards KRAS-mutated human lung-cancer cells (A549) was studied. The results indicate the existence of intracellular singlet oxygen inflicted anticancer PDA, which is apparent through the upregulation of intracellular reactive oxygen species (ROS) and the downregulation of both intracellular superoxide dismutase (SOD) and intracellular reduced glutathione (GSH) levels. The trends obtained from both SOD and GSH assays were indicators of therapeutic defence against oxidative stress via neutralizing superoxide anions (SOA).

The cytotoxic activities of KP1019 and other Ru(III) drugs are believed to be associated with their binding with DNA. Here, we report the density functional theory (DFT) study of reactions of KP1019 drug at the O6 and O8 sites of 8-oxoguanine (8-oxoG) and the O8 site of 8-oxoadenine (8-oxoA). 8-OxoG is predominantly formed in oxidative stress and can cause mutation and cancer. It is found that the barrier free energies (ΔGb) of these reactions obey the following trend: O8 (8-oxoG) < O8 (8-oxoA) < O6 (8-oxoG), at different levels of theory in gas phase and aqueous media. The ΔGb of reaction at the O8 (8-oxoG) is found to be 10.96 (13.81) kcal/mol at the M06-2X/(LanL2DZ+6-311+G**) level of theory in gas phase (aqueous media). The rate constant of reaction at the O8 (8-oxoG) site in aqueous media is 4.6 × 102 s−1. The reaction free energies (ΔGf) and reaction enthalpies (ΔHf) of all the reactions are appreciably negative in both gas phase and aqueous media which indicate that the reaction of mono-aquated KP1019 at the O6 and O8 sites of 8-oxoG as well as at the O8 site of 8-oxoA would occur spontaneously. Further, our calculations demonstrate that KP1019 would react with 8-oxoG more favourably as compared with guanine. Thus, it predicts that the main mechanism of the action of KP1019 drug might be due to its binding with the O8 site of 8-oxoG in biological media.