Structural insight into binding mode of inhibitor with SAHH of Plasmodium and human: interaction of curcumin with anti-malarial drug targets

Abstract

S-adenosyl-L-homocysteine hydrolase of Plasmodium falciparum (PfSAHH) is a potential drug target against malaria, and selective inhibition of PfSAHH is the excellent strategy to prevent the growth of parasite inside the host. Therefore, a comparative analysis of human S-adenosyl-L-homocysteine hydrolase (HsSAHH) and PfSAHH has been performed to explore the structural differences. Structural superimposition of PfSAHH and HsSAHH has generated the RMSD of 0.749 Å over 394 alpha carbon pairs. Residues of PfSAHH from position Tyr152 to Lys193 aligned with insertion/deletion region in HsSAHH, and these extra residues results in an extent of variation in cavity region of PfSAHH. Nicotinamide adenine dinucleotide (NAD) was observed to form hydrogen bonding with Thr201, Thr202, Thr203, Asn235, Val268, Glu287, Asn322, Ile343, Asn391, Lys473, and Tyr477 and also forms hydrophobic interactions with Val268, Ile288, and Thr320 of PfSAHH. In comparison to HsSAHH, Asn322, Lys473, and Tyr477 residues of PfSAHH are unique in interaction with NAD. 2-Fluoroaristeromycin and other analogues of aristeromycin have shown the good binding affinity for both enzymes. Structural differences between PfSAHH and HsSAHH might be employed to design the potential inhibitor of PfSAHH. To find the target enzyme responsible for an anti-malarial effect, molecular docking and interaction analysis of curcumin were performed with 34 drug targets of P. falciparum. Curcumin shows high affinity for binding with HGPRT of PfHGPRT, and an anti-malarial effect of curcumin might be due to binding with PfHGPRT.

Stereochemistry in the Reaction of the myo-Inositol Phosphate Synthase Ortholog Ari2 during Aristeromycin Biosynthesis

“…Aristeromycin ( 1 ) is a carbocyclic nucleoside antibiotic produced by Streptomyces citricolor (Figure A) . Aristeromycin effects its biological activity against bacteria, viruses, and tumor cells by inhibiting S -adenosyl- l -homocysteine hydrolase. − The compound exhibits the unique structural feature of a five-membered cyclitol moiety, which is connected to an adenine ring to form an adenosine mimic . Genome sequence analysis of the producer strain S. citricolor NBRC 13005 revealed that the myo -inositol phosphate synthase (MIPS) ortholog-containing biosynthetic gene cluster is responsible for the biosynthesis of aristeromycin .…”

Curcumin and Its Derivatives as Potential Antimalarial and Anti-Inflammatory Agents: A Review on Structure–Activity Relationship and Mechanism of Action

“…The identification of therapeutic targets involved in malarial infection can provide a better understanding of the inhibitory mechanism of antimalarial agents (Figure 22) [39,106]. The current knowledge on the action of curcumin derivatives is limited, as their hosttargeting mechanisms have not been entirely established (Table 4) [41,90,107]. Therefore, future research that can explain an in-depth understanding of the molecular-level mechanism of action of curcumin and its bioactive derivatives will not only help in the development of potent antimalarial and anti-inflammatory agents [108] but also for other diseases [109][110][111].…”