Computational Study of Indole‐Quinoline Scaffolds with Tubulin Protein

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ABSTRACT Novel indole‐quinoline molecules were designed, and a molecular docking study has been performed to find out the binding affinity toward colchicine binding sites of the tubulin protein, as well as Lipinski parameters analysis has also been done. The comparative molecular docking analysis showed that all the designed compounds have a higher predicted binding affinity than the standard drug colchicine, and among all compounds, 6g has a better binding score. Similar to other compounds, 6e, exhibited a good binding, while 6f shown a relatively lower binding because of large groups that cause steric clash. Many compounds, like 6a, 6c, and 6d surpassed the affinity of colchicine that indicates the feasibility of the these compounds to be used as tubulin‐binding agents. This study evaluated the binding affinity of indole‐quinoline derivatives ((6a‐g) toward tubulin, using colchicine as a reference. Molecular docking (RMSD <2.0 Å) showed that all compounds scoring better than colchicine (−6.76). 6g had the best score (−7.27) due to optimal side chain fit, followed by 6e (−7.01), while 6f scored lowest (−6.56) due tosteric hindrance. Structure–activity analysis linked side chain and aromatic modifications to binding efficiency. Physicochemical profiling indicated higher molecular weight, lipophilicity, and polarity than colchicine, suggesting improved permeability and potency. 6g and 6e are promising leads for further optimization.

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