Rationalizing the crosslinking reaction of an α,β unsaturated carbonyl of clovamide from Adansonia digitata L. and the cysteine residue of HIV-1 integrase enzyme

Abstract

Abstract In this study, clovamide was identified for the first time in Adansonia digitata L. fruit pulp using the UHPLC-q-TOF-MS. The inhibition potential of the naturally occurring clovamide, specifically in the SE and SZ configurations and their yet to be identified enantiomers ( RE and RZ ) on HIV-1 integrase (HIV-1 INT) were investigated using molecular docking studies. The results revealed that all the four stereoisomers of clovamide bind to key residues crucial for the catalytic activity of HIV-1 INT (ASP64, ASP116 and GLU152) as well as other significant residues including, LYS152 and LYS159. This indicates that clovamide has the potential to inhibit this enzyme and possibly slow down HIV-1 replication. Interestingly, the docking results showed that CYS65 was in close proximity to ASP64, allowing nearly all isomers of clovamide to interact with this residue. This suggested a potential crosslinking reaction via Michael addition between clovamide and CYS65. The consistent proximity of all ligands to CYS65 in the studied protein throughout the entire molecular dynamics simulation period also showed the potential of permanent covalent bonds formation via a Michael addition reaction. Density functional theory modelling confirmed that the α,β-unsaturated carbonyl group of clovamide and cysteine interact, forming a clovamide-integrase adduct, potentially leading to irreversible inhibition of HIV-1 INT. This study not only highlighted the potential of clovamide as an inhibitor of HIV-1 INT but also demonstrated that clovamide possesses various functional groups that can be exploited in different biological activity studies. Findings of this study suggest that clovamide and its stereoisomers could be valuable candidates for the development of new antiretroviral therapies, offering a novel approach to overcoming drug resistance through multiple inhibition mechanisms.