Natural Compounds as Inhibitors of Plasmodium Falciparum Enoyl-acyl Carrier Protein Reductase (PfENR): An In silico Study

Abstract

Demand for a new anti-malarial drug has been dramatically increasing in the recent years. Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) plays a vital role in fatty acid elongation process, which now emerged as a new important target for the development of anti-microbial and anti-parasitic molecules. In the present study, 19 compounds namely alginic acid, atropine, chlorogenic acid, chrotacumine A & B, coenzyme Q 1 , 4-coumaric acid, curcumin, ellagic acid, embelin, 5-O-methyl embelin, eugenyl glucoside, glabridin, hyoscyamine, nordihydroguaiaretic acid, rohitukine, scopolamine, tlatlancuayin and ursolic acid were evaluated on their docking behaviour on P. falciparum enoyl-acyl carrier protein reductase (PfENR) using Auto dock 4.2. The docking studies and binding free energy calculations exhibited that glabridin gave the highest binding energy (-8.07 kcal/mol) and 4-coumaric acid in contrast showed the least binding energy (-4.83 kcal/mol). All ligands except alginic acid, ellagic acid, hyoscyamine and glabridin interacted with Gln409 amino acid residue. Interestingly four ligands namely coenzyme Q 1 , 4-coumaric acid, embelin and 5-O-methyl embelin interacted with Gln409 amino acid residue present in both chains (A & B) of PfENR protein. Thus, the results of this present study exhibited the potential of these 19 ligands as P. falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitory agents and also as anti-malarial agents.

Future antimalarials fromArtemisia? A rationale for natural product mining against drug-refractoryPlasmodiumstages

“…27,29 Mechanistically, the fact that 5-O-caffeoylquinic acid (syn. CGA) inhibits bacterial FabG 139 (keeping in mind the general sensitivity of apicoplast enzymes, including Fabs, towards antibacterials) 121,140,141 and is also predicted to bind plasmodial FabI in silico, 142 suggests FASII inhibition and possible anti-apicoplast effects for CGAs in Plasmodium. Regarding a possible mitochondrial inhibition, CGAs induce mitochondrion-dependent apoptosis in cancer cells via the disruption of its inner membrane potential and production of ROS, in addition to other cytotoxic effects (e.g., inhibition of the PI3K/AKT/mTOR pathway) [143][144][145][146] which could be relevant in host cells and Plasmodium parasites altogether.…”

“…Impairment of specic Plasmodium stages via the inhibition of putative pharmacological targets (e.g., prenyl-associated enzymes, FASII) by A. annua and A. afra metabolites has been discussed previously. [80][81][82][83][84][85]102,116,142 The redox-cycling properties of several phytochemicals present in their infusions could also account for the observed loss of viability of drug-refractory parasite stages, known to be highly vulnerable to ROS-generating inhibitors such as primaquine metabolites 50,51,193,194 and methylene blue. 37,[195][196][197][198][199] These inhibitors rely on host or parasite reductases for their continuous reduction into pro-oxidant species in presence of a non-limiting reducing cofactor.…”

Artemisinin-independent inhibitory activity ofArtemisiasp. infusions against differentPlasmodiumstages including relapse-causing hypnozoites

“…On the other hand, certain anti-plasmodial flavonoids from both Artemisia species (i. e., cynaroside, chrysoeriol) possess ROS-scavenging capability, with mitoprotective and antiapoptotic effects, [82][83][84] leading to tentatively exclude mitochondrion-disrupting mechanisms for these compounds in the parasite. The molecular targets of chlorogenic acids in Plasmodium are unknown, but the fact that chlorogenic acid itself was predicted to bind FabI in silico 85 validates their investigation for anti-apicoplast effects related to FASII inhibition. Regarding possible mitochondrial effects, chlorogenic acid and congeners show cytotoxicity and induce mitochondrion-dependent apoptosis in cancer cells via ROS production and collapse of the inner membrane potential, in addition to other effects (e. g., inhibition of the PI3K/AKT/mTOR pathway, activation of PKC).…”

Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum

“…A derivative of p -coumaric acid, methyl p -coumarate, presents activity against P. falciparum [ 42 ]. There are also reports regarding p -coumaric acid and inhibition of P. falciparum dihydropteroate synthase [ 43 ]. The aim of the study was to prepare p -coumaric acid derivatives and evaluate their antiprotozoal activity.…”