Ligand-protein interactions of plant-isolated (9z,12z)-octadeca-9,12-dienoic acid with B-ketoacyl-Acp synthase (KasA) in potential anti-tubercular drug designing

Abstract

Mycobacterium tuberculosis remains one of the world’s contributors to mortality. With the emergence of SARS-CoV-2 coinfections, patients with TB are predisposed to being more heavily weighed down by COVID-19 disease and its opportunistic coinfections. The severity of the disease coupled with drug resistance on the currently used drugs war- rants for the search for alternative remedies from synthetic agents, semisynthetics and natural products that include plants. Africa is rich in plant diversity with a promise as sources of drug agents, one of which is Eichhornia crassipes . This work aimed at isolating a fatty acid and dock it to β-ketoacyl-ACP synthase for possible anti-TB drug development prospects using computational tools. (9z,12z)-Octadeca-9,12-dienoic acid was isolated from Eichhornia crassipes for the first time using chromatographic techniques and identified us- ing 1D and 2D NMR spectroscopic methods ( 1 H NMR, COSY, HSQC, HMBC and 13 C NMR). The compound was then docked to β-ketoacyl-ACP synthase (KasA), an essential mem- ber of the b-ketoacyl synthases encoded in the M. tuberculosis genome in comparison with its co-crystallized ligand JSF-3285, also for the first time. (9z,12z)-Octadeca-9,12-dienoic acid interacted with only phenylalanine239 and proline201 while JSF-3285 interacted with proline201, glutamine120, alanine119, leucine116, glutamine199, histadine345, phenylala- nine239, glycine240 and glycine200. (9z,12z)-Octadeca-9,12-dienoic acid had a ligand ef- ficiency of 0.24, compared to the co-crystallized ligand’s 0.36. The compound was too flexible and elongated with -4.72 KCalmol −1 binding energy. Despite some unfavourable physico-chemical properties, the compound still provides reliable interactions that only require logical structural modifications by the addition of polar regions amongst others to increase interactions and ligand efficiency, which can consequently stand to be a bet- ter potential drug lead. For the first time, plant-based (9z,12z)-Octadeca-9,12-dienoic acid isolated from Eichhornia crassipes was shown to interact fairly well with β-ketoacyl-ACP synthase and proved to be a potential starting material from which anti-tubercular drugs can be designed