RESUMO
Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. -49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with ΔGbinding values of -93.0, -92.6, -93.8, -92.2, and -90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile.
RESUMO
The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues −namely, chetomin A-D− as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate.