Interaction of 2'-deoxyguanosine with cis-2-butene-1,4-dial: Computational approach to analysis of multistep chemical reactions

cis-2-Butene-1,4-dial represents a microsomal metabolite of furan, an industrially important chemical found in cigarette smoke, air pollution, and also in canned or jarred food. It is expected to be a human carcinogen. Aim. Investigation an effect of cis-2-butene-1,4-dial on the 2'-deoxyguanine which is a model of DNA site. Methods. Optimization of reaction species molecular structures, spectral parameters and Gibbs free energy calculations were performed using Gaussian09 program. Systems of differential equations for kinetics generation were solved using Mathcad15 program. Results. The predicted mechanism of the reaction of cis-2-butene-1,4-dial with 2'-deoxyguanine consists of four-step process formation of four diastereomeric primary adducts and further base-mediated five-step transformation of the primary adducts to the secondary one. The reaction kinetics, which allows defining theconcentration change of any reaction species was calculated. Conclusions. Under physiological conditions the interaction between cis-2-butene-1,4-dial and 2'-deoxyguanine leads to the formation of a stable adduct which could be responsible for the furan genotoxicity.цис-2-Бутен-1,4-діаль є мікросомним метаболітом фурану – промислово важливого хімікату, виявленого в сигаретному димі, забрудненому повітрі, а також, іноді, в консервованих або банкових продуктах. Його вважають потенційним канцерогеном для людини. Мета. Дослідити вплив цис-2-бутен-1,4-діалю на 2'-де- зоксигуанозин – модельний фрагмент ДНК. Методи. Оптимізацію структури учасників реакції, розрахунки спектральних параметрів і вільної енергії Гіббса виконано в програмі Gaussian09. Системи диференційних рівнянь для отримання кінетичних даних вирішували з використанням програми Mathcad15. Результати. Прогнозований механізм реакції цис-2-бутен-1,4-діалю з 2'-дезок- сигуанозином реалізується у чотири стадії, протягом яких утворюються чотири діастереоізомерних первинних адукти, та наступної п’ятистадійної трансформації, каталізованої основами, первинних адуктів у вторинні. Розраховано кінетику реакції, що дозволяє визначати зміни концентрації будь-якого учасника реакції. Висновки. За фізіологічних умов взаємодія між цис-2-бутен-1,4-діалем і 2'-дезоксигуанозином призводить до утворення стабільного адукта, який може відповідати за генотоксичність фурану.цис-2-Бутен-1,4-диаль является микросомным метаболитом фурана – промышленно важного химиката, обнаруженного в сигаретном дыме, загрязненном воздухе, а также, иногда, в консервированных или баночных продуктах. Его считают потенциальным канцерогеном для человека. Цель. Исследовать влияние цис-2- бутен-1,4-диаля на 2'-дезоксигуанозин – модельный фрагмент ДНК. Методы. Оптимизацию структуры участников реакции, расчеты спектральных параметров и свободной энергии Гиббса выполняли в программе Gaussian09. Системы дифференциальных уравнений для получения кинетических данных решали с помощью программы Mathcad15. Результаты. Реакция цис-2-бутен-1,4- диаля c 2'-дезоксигуанозином проходит в четыре стадии с формированием четырех диастереоизомерных первичных аддуктов и последующей, катализируемой основаниями, пятистадийной трансформации первичных аддуктов во вторичные. Рассчитана кинетика реакции, что позволяет определять изменения концентрации любого участника реакции. Выводы. При физиологических условиях взаимодействие между цис-2-бутен-1,4-диалем и 2'-дезоксигуанозином приводит к образованию стабильного аддукта, который может отвечать за генотоксичность фурана

QSAR analysis of the toxicity of nitroaromatics in Tetrahymena pyriformis : structural factors and possible modes of action

The Hierarchical Technology for Quantitative Structure - Activity Relationships (HiT QSAR) was applied to 95 diverse nitroaromatic compounds (including some widely known explosives) tested for their toxicity (50% inhibition growth concentration, IGC50) against the ciliate Tetrahymena pyriformis. The dataset was divided into subsets according to putative mechanisms of toxicity. Classification and Regression Trees (CART) approach implemented within HiT QSAR has been used for prediction of mechanism of toxicity for new compounds. The resulting models were shown to have ~80% accuracy for external datasets indicating that the mechanistic dataset division was sensible. Then, Partial Least Squares (PLS) statistical approach was used for the development of 2D QSAR models. Validated PLS models were explored to (i) elucidate the effects of different substituents in nitroaromatic compounds on toxicity; (ii) differentiate compounds by probable mechanisms of toxicity based on their structural descriptors; (iii) analyze the role of various physical-chemical factors responsible for compounds’ toxicity. Models were interpreted in terms of molecular fragments promoting or interfering with toxicity. It was also shown that mutual influence of substituents in benzene ring plays the determining role in toxicity variation. Although chemical mechanism based models were statistically significant and externally predictive (R2ext=0.64 for the external set of 63 nitroaromatics identified after all calculations have been completed), they were also shown to have limited coverage (57% for modeling and 76% for external set)

Structural diversity of the region encompassing DIS, SD and Psi hairpins in HIV and SIV genomes

We investigated in silico the secondary structure of the region encompassing DIS, SD and Psi hairpins in HIV-1 genomes of rare groups N, O and P, HIV-2 genomes and SIV genomes from chimpanzees, gorillas and monkeys. We found that the structure of this region in SIVcpzptt genomes of the 1st and the 2nd clusters is similar to that in HIV-1 genomes of groups M and N, respectively. Further, the structure of the region encompassing DIS, SD and Psi hairpins is similar in HIV-1 genomes of groups O and P and SIVgor genomes. Here we report that the DIS hairpin and truncated Psi hairpin are conserved in all HIV-1 and SIVcpz/gor genomes studied, while only the sequence of the splice donor site, but not the architecture of the SD hairpin involving this signal is conserved in HIV-1N/O/P and SIVcpz/gor genomes.A study on the 5′ leader structure in genomes of 28 different SIV lineages infecting monkeys showed that the domain closed by U5-AUG duplex can form in all these genomes. This domain mainly consists of 2 subdomains, one of which includes the signal PBS (PBS subdomain) and another contains a putative DIS hairpin (DIS subdomain). DIS subdomains contain 1–8 hairpins. None of them is similar to those in HIV-1 or SIVcpz/gor genomes. The palindrome GUGCAC was found only in SIVdrl/mnd-2, the GACGC-GCGUC duplex (Sakuragi et al., 2012) – only in SIVrcm/drl/mnd-2 and a putative 5′ G-quadruplex – in SIVdeb/drl/rcm/stm genomes. In genomes of eight SIV lineages, DIS hairpin has palindrome UGCGCA.Studies on the 5′ leader in 64 HIV-2 genomes of different subtypes showed, in particular, that this region has sequences of a putative 5′ G-quadruplex and a putative duplex similar to the GACGC-GCGUC duplex. The secondary structures of the region encompassing DIS, SD and Psi hairpins in HIV-2 genomes of subtype B and recombinant 01_AB are similar and differ from that in genomes of subtype A