3D-QSAR and Molecular Docking Analysis for Natural Aurone Derivatives as Anti-Malarial Agents

Three-dimensional quantitative structure-activity relationships were studied on 35 natural aurone derivatives by the Topomer CoMFA method to establish the 3 D-QSAR models, and exerting potent affections as Qo site inhibitors in cytochrome b activity for anti-malaria. The cross-validated q2 value of the Topmer CoMFA model = 0.539, the non-cross-validated r2 = 0.793, rpred2 = 0.960, which revealed the model has good stability and predictability. The steric and electrostatic field visualization provided by the Topomer CoMFA model intuitively revealed the effects of different substituent structures. Using this information for molecule design, we theoretically obtained some new aurone derivatives as antimalarial drugs with higher activity. Furthermore, molecular docking was employed to explore the binding requirements between the ligands and the receptor protein. We obtained space relations by hydrogen bonds and hydrophobic interactions between aurone derivatives and the active site residues. The observations from these QSAR and molecular docking studies can be further used to design promising antimalarial drugs.</p

Exploration of anti-tumour inhibitors from colchicine derivatives based on 3D-QSAR, molecular docking and molecular dynamics simulations

Microtubulin is an important research target for anti-tumour drugs, which can be used to inhibit microtubulin polymerisation and improve the efficacy of tumour therapy. In this paper, 61 microtubule protein inhibitors with anticancer activity are selected as the data set for building a stable and effective QSAR (Topomer CoMFA) model, resulting in a Topomer CoMFA model with validation coefficients of q2 = 0.737 and r2 = 0.922. Fifteen new inhibitors with theoretically high activity are designed by screening the zinc database for new fragments with good activity through the contribution descriptors obtained by Topomer CoMFA. After simulating the binding affinity and interaction of the inhibitors with the proteins by molecular docking, all these compounds formed strong interactions such as hydrogen bonds with multiple amino acids in the receptor proteins. Furthermore, molecular dynamics results show that the predicted highly active compounds exhibited stable and favourable binding patterns to the active pocket. In addition, these new compounds exhibit good ADMET properties. The present work establishes a reliable QSAR model for computational simulation screening of microtubulin drug development and provides a basis for further access to novel microtubulin inhibitors.</p

Combining QSAR techniques, molecular docking, and molecular dynamics simulations to explore anti-tumor inhibitors targeting Focal Adhesion Kinase

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (q2= 0.715, r2= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (q2= 0.707, r2= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors. Communicated by Ramaswamy H. Sarma</p