Abstract Tubulin plays an indispensable role in regulating various important cellular processes. Recently, it is known as a hopeful therapeutic target for the rapid division of cancer cells. Novel series of 2-oxoquinoline arylaminothiazole derivatives have been recently identified as promising tubulin inhibitors with potent cytotoxicity activity against HeLa cancer cell line. In this study, a 3D-QSAR approach by using CoMFA and CoMSIA techniques was applied to the reported derivatives to understand their pharmacological essentiality contributing to the tubulin inhibition activity and selectivity. The optimum CoMFA and CoMSIA models were found to have significant statistical reliability and high predictive ability after internal and external validation. By analyzing the contour maps, the electrostatic and hydrophobic interactions were found to be crucial for improving the inhibitory activity and four novel tubulin inhibitors (Compounds D1, D2, D3, and D4) were designed based on the validated 3D-QSAR models. Moreover, the docking findings showed that residues Gln136, Val238, Thr239, Asn167, Val 318 and Ala 316 played important roles for quinoline binding to tubulin. Among the newly designed compounds, compound D1 with the highest total scoring was subjected to detailed molecular dynamics (MD) simulation and compared to the most active compound. The conformational stability of compound D1 complexed with tubulin protein was confirmed by a 50-ns molecular dynamics simulation, which was congruent with molecular docking.

Resumen La tubulina juega un papel indispensable en la regulación de varios procesos celulares importantes. Recientemente, se le ha reconicodo como un agente promisorio para atacar la rápida división de las células cancerosas. Últimamente se ha identificado una nueva serie de derivados de arilaminotiazo-2-oxoquinolina como potenciales inhibidores de la tubulina, con una elevada actividad citotóxica contra la línea celular de cáncer HeLa. En este estudio, se aplicó a los derivados informados un estudio 3D-QSAR mediante el uso de técnicas CoMFA y CoMSIA para comprender los factores farmacológicos que contribuyen a la actividad como inhibidor y selectivo de la tubulina. Se encontró que los modelos CoMFA y CoMSIA óptimos tienen una confiabilidad estadística significativa y una alta capacidad predictiva después de la validación interna y externa. Al analizar los mapas de contorno, se descubrió que las interacciones electrostáticas e hidrófobas eran cruciales para mejorar la actividad inhibidora y se diseñaron cuatro nuevos inhibidores de la tubulina (compuestos D1, D2, D3 y D4) basados en los modelos 3D-QSAR validados. Además, los hallazgos de acoplamiento mostraron que los residuos Gln136, Val238, Thr239, Asn167, Val 318 y Ala 316 desempeñaron papeles importantes en la unión de la quinolina a la tubulina. Entre los compuestos de nuevo diseño, el compuesto D1 con la puntuación total más alta se sometió a una simulación detallada de dinámica molecular (MD) y se comparó con el compuesto más activo. La estabilidad conformacional del compuesto D1 unido a la proteína tubulina se confirmó mediante una simulación de dinámica molecular de 50 ns, que fue congruente con el acoplamiento molecular.

Abstract: Dye-sensitized solar cells (DSSCs) based on triphenylamine (TPA) as a donor group linked with the acceptor cyanoacrylic acid electron acceptor by 2,2’-bithiophene as π-bridged (D-π-A) has been investigated by Density Functional Theory (DFT) at the B3LYP/6-311G(d,p) level of theory, to establish the conformational orientation of cyanoacrylic acid group as well as evaluate the effect of planarizing the 2,2’-bithiophene unit in position 3 and 3’ by electron withdrawing or donor groups on the electronic structure properties of ground and doping(n,p) states. Also, the Time Dependent Density Functional Theory (TD-DFT) at the CPCM-TD-CAM-B3LYP//CAM-B3LYP/6-311G(d,p) level of theory were selected to modulate the electronic absorption spectra and charge-transfer capabilities of the molecules analyzed in the present work. The results indicate that adding an auxiliary donor or withdrawing group to the 2,2’-bithiophene in the (D-π-A) arrangement allow to modify the LUMO’s energy of the dyes, while the HOMO's energy is slightly affected.

ABSTRACT Four acceptor-donor organic conjugated molecules based on thieno[3,4-b]pyrazine-terthienyls were analyzed in order to explore the effect of the donor substituent on their molecular structures, electronic and optical properties. Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD/DFT) calculations were carried out employing the B3LYP hybrid functional in combination with the 6-31G(d,p) basis set. The results suggests that the addition of electron-donating substituents to the conjugated molecules can diminish their energy gap value, which is beneficial to the photon harvesting. The lowest-lying absorption spectra of compounds substituted with electron donor groups exhibited a red-shift and a high oscillation factor compared with the unsubstituted molecule. Additionally, the ionization potential (IP), electron affinity (EA), reorganization energy (λ) and open-circuit voltage (Voc) of the molecules were evaluated. According to these values, the molecules show good photovoltaic properties, and efficient charge transfer for hole and electron and balanced charges.