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Vinblastine (VLB), a cytotoxic alkaloid is used extensively against various cancer types and the crystal structure of its tubulin complex is already known. Multitarget affinity of vinblastine has been investigated and the nature of binding with biological receptors namely, duplex DNA and Human serum albumin (HSA) has been compared to the binding characteristics of its known complex with natural high affinity receptor tubulin using molecular docking and QM–MM calculations. VLB is found to interact with DNA as well as HSA protein, though, with weaker affinity as compared to tubulin. Analysis of various docked complexes revealed that the H-bonds and cation–pi bonds do not have significant contribution to the binding interactions and despite its large size, VLB remains in relaxed conformation and fits in the hydrophobic regions on the receptors. [ABSTRACT FROM AUTHOR]

We have recently reported a new chemotype of a potent topoisomerase I poison with compound 1 as a potential anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1 , we report design and synthesis of metabolically stable Top1 poison 3. Newly identified Top1 poison 3 exhibits t 1/2 of 69.1 min in human liver microsomes in comparison to compound 1 with t 1/2 of 9.9 min. Molecular dynamic study of the newly optimized Top1 poison 3 was performed to get the insight into the stability of the binding pose in the active site. Compound 3 was able to trap DNA-Top1 cleavage complex and found to be less cytotoxic in non-cancerous cell line as compared to compound 1. Image 1 • Strategic development of potent Top1 poison with enhanced metabolic stability. • Validation of compound 3 as Top1 poison by ex vivo plasmid DNA cleavage assay. • Molecular Dynamic simulations of compound 3 in the active site. • Lead compound 3 found to be less cytotoxic in non-cancerous cell line. [ABSTRACT FROM AUTHOR]