Exploring dual inhibitory role of febrifugine analogues against Plasmodium utilizing structure-based virtual screening and molecular dynamic simulation

Abstract

Malaria is an endemic disease caused by the protozoan parasite Plasomodium falciparum. Febrifugine analogues are natural compound obtained from the traditional Chinese herbs have shown significant antimalarial and anticancerous efficacy in experimental model. Development of resistance against the existing antimalarial drug has alarmed the scientific innovators to find a potential antimalarial molecule which can be further used by endemic countries for the elimination of this disease. In this study, structure-based virtual screening and molecular dynamics (MD) base approaches were used to generate potential antimalarial compound against plasmepsin II and prolyl-tRNA synthetase of Plasmodium. Here, we have docked series of febrifugine analogues (n = 11,395) against plasmepsin II in three different docking modes and then it was compared with previously reported target prolyl-tRNA synthetase. Extra precision docking resulted into 235 ligands having better docking score were subject for QikProp analysis. Better ligands (n = 39) obtained from QikProp analysis were subject for ADMET prediction and docking protocol validation through the estimation of receiver operator characteristics. In the later stage, 24 ligands obtained from ADMET study were subject for the estimation of binding energy through MM-GBSA and same were also docked against prolyl-tRNA synthetase to get compounds with dual inhibitor role. Finally, MD simulation and 2D fingerprint MACCS study of two best ligands have shown significant interaction with plasmepsin II and homology against known active ligand with noteworthy MACCS index, respectively. This study concludes that FA12 could be potential drug candidate to fight against Plasmodium falciparum parasites.

Designing of a next generation multiepitope based vaccine (MEV) against SARS-COV-2: Immunoinformatics andin silicoapproaches

“…An adjuvant (45 amino acid long β-defensin) was linked with the help of EAAAK linker at the start (to the N-terminal of the MEV). EAAAK linker reduce interaction with other protein regions with efficient separation and increase stability [73, 74]. The vaccine’s immunogenicity may increase with an adjuvant.…”

“…The vaccine’s immunogenicity was increased with an adjuvant. An adjuvant and a CTL epitope were connected to the N-terminal of the structure of the vaccine by using the EAAAK linker to reduce interaction with other protein regions with efficient separation 50, 51 . After the addition of linkers and adjuvant final construct was 505 amino acid long (Figure 3).…”

Multiepitope-Based Subunit Vaccine Design and Evaluation against Respiratory Syncytial Virus Using Reverse Vaccinology Approach

“…An adjuvant (45 amino acid long β-defensin) was bound with the aid of the EAAAK linker at the start (to the MEV N-terminal). EAAAK linker reduces connection with other protein areas with efficient detachment and increases stability [88,89]. The vaccine's immunogenicity may increase with an adjuvant.…”

Novel Immunoinformatics Approaches to Design Multi-epitope Subunit Vaccine for Malaria by Investigating Anopheles Salivary Protein

“…Malaria still remains one of the most devastating and deadly infectious disease, which is characterized by the intermittent high fevers and it’s another form namely cerebral malaria, leads to the neurological complications such as brain injury and coma 1 , 2 . As per the World Health Organization (WHO) latest estimate, almost 212 million cases of malaria along with 42,900 deaths were reported in December 2016 among 91 countries, worldwide 3 .…”