Design, Molecular Docking, and Structure–Property Analysis of Novel Combretastatin A-4 Derivatives

Introduction. One of the most promising areas of a targeted approach to the treatment of malignant neoplasms is the inhibition of tubulin polymerization. In this regard, the aim of this study is the molecular design of new derivatives of combretastatin A-4 to identify compounds with high affinity for the colchicine site of β-tubulin. Materials and methods. Molecular docking was performed in the Glide software package (Schrödinger Maestro module). The crystallographic structure of the tubulin-combretastatin A4 complex (PDB ID 5LYJ) was used as a receptor. To identify the structure–property relationships, the following descriptors were calculated: the number of hydroxyl and methoxyl groups; the presence of C=C bonds, cyclopropane and 1,2,5-oxadiazole rings. The ADME characteristics were calculated using the ADMETlab resource. Results. Of the 96 compounds examined, 7 molecules demonstrated better (more negative) GlideScore values than combretastatin. The presence of methoxyl groups negatively correlates with the value of GlideScore, making the main contribution to affinity due to hydrophobic interactions with the binding site. Hydroxyl groups also contribute to improved binding to the target due to the formation of additional hydrogen bonds. Replacing the double bond with a cyclopropane fragment results in compounds with comparable affinity (GlideScore ≈ – 8.2 kcal/mol). In contrast, oxadiazole analogues, on average, exhibit worse binding rates. Discussion and conclusion. Compounds containing a cis-alkene bridge and a combination of hydroxy and methoxy substituents demonstrated GlideScore values superior to combretastatin A-4, which makes them candidates for further synthesis and experimental study in vitro.