In-silico Approach for Evaluation of Antimalarial Potential of Costunolide Synthase Enzyme and Sesquiterpene Lactones from Cichorium intybus

Abstract

Background: Cichorium intybus is a perennial herb in the Asteraceae family that has significant ethano-medical properties and is utilized in Ayurveda and Unani therapy. The enzyme costunolide synthase contributes in the biosynthesis pathway of sesquiterpene lactones, which is thought to give the plant antimalarial action. Methods: This work uses several in-silico techniques along with docking experiments to show the structural and physiochemical characteristics of the enzyme costunolide synthase. Costunolide synthase protein interacts with lactucin and lactucopicrin with lower energy interactions of -4.99 kcal/mol for total 3 hydrogen bonds and -6.55 kcal/mol for total 2 hydrogen bonds, respectively. One domain named CYP 450 has been found which catalyzes a variety of oxidative reactions of a large number of structurally different compounds that are both endogenous and exogenous from all major domains of life. The mitochondrial cellular localization of protein was revealed with a maximum score of 1.833. Results: The phylogenetic study revealed that the enzyme costunolide synthase from Cichorium intybus has a greater resemblance to Cichorium endivia and Lactuca sativa of costunolide synthase. Molecular docking findings of sesquiterpene lactones (lactucin and lactucopicrin) with Plasmepsin II protein of P. falciparum parasites after clinical trials with sesquiterpene lactones may give the more evidences and explanations for the active involvement of lactucin and lactucopicrin as an antimalarial compound. Conclusion: This research will be used in future wet lab studies to figure out how the costunolide synthase enzyme regulates sesquiterpene lactones and to investigate additional regulatory enzyme involved in the synthesis of sesquiterpene lactones.

Computational exploration of microsomal cytochrome P450 3A1 enzyme modulation by phytochemicals of Cichorium intybus L.: Insights into drug metabolism

“…The protein has 384 helices, 373 beta sheets and 56 twists, and coils with 76.5% (helix), 74.3% (sheets) and 11.2% (turns and coils) secondary structures with a main sequence of 50 amino acids taken at one wide band at a time (Figure 1). The total molecular weight (MW) was estimated to be 57,675.52 Da with a theoretical isoelectric point of 8.82, which has a direct impact on protein solubility in water or salt solutions and is beneficial for protein purification (Pathak, Arora et al., 2023, Pathak, Singh et al., 2023).…”

“…Since the 3D structure of CYP3A1 protein of rat was not present in the Protein Data Bank, the Rapter X server was used to generate the 3D model with a p ‐value of 4.0e‐11 using the 4d6zA template. The total uGDT (GDT) value of 412/82 demonstrated its stability, as the uGDT value must be larger than 100 and the GDT value must be greater than 50 with a low p value for the 3D model of protein to be stable (Figure 2) (Pathak, Arora et al., 2023; Pathak, Singh et al., 2023). In 2004, only three structures of CYP were known, as highlighted in the study by Hillisch et al.…”

“…(2016). The three‐dimensional model of CYP3A1 protein was constructed using the Raptor X software (Pathak, Arora et al., 2023, Pathak, Singh et al., 2023).…”

“…Chicory, or Cichorium intybus L., is a herbaceous perennial in the family Asteraceae that has both culinary and therapeutic uses (Pathak & Singh, 2022). It is 40–100 cm tall and often has beautiful blue flowers; rarely does it have white or pink blossoms (Pathak, Arora et al., 2023, Pathak, Singh et al., 2023). Fresh chicory is said to normally contain 68% inulin, 14% sucrose, 5% cellulose, 6% protein, 4% ash, and 3% other compounds, but dried chicory is said to contain about 98% inulin and 2% other chemicals (Pathak et al., 2022).…”

“…According to a classical medicinal specialist, it has been used for many years in folk remedies from North Africa to South Asia with the benefits of diuresis, improving digestion, treating jaundice, and enhancing kidney and liver activity. It is important to mention that Cichorium intybus L. has been shown in the literature to have a broad range of pharmacological activities, including hepatoprotective, anti‐inflammatory, anti‐malarial, and anti‐diabetic actions (Pathak, Arora et al., 2023, Pathak, Singh et al., 2023). Although C. intybus L. possesses specific hepatoprotective properties, additional research is still needed to determine how it affects cytochrome P450 (CYP) modulation pathways or drug‐metabolizing enzymes.…”