In this study, de novo analogue design approach was adopted to find out novel chemical entities for the inhibition of cysteine protease falcipain-2 protein for Plasmodium falciparum. In this purpose a set 34 cysteine protease falcipain-2 protein inhibitors were collected from the literature and molecular docking performed. High binding energy complexes were used for analogue design in e-LEA3D: Chem Informatic Tools and Databases (http://chemoinfo.ipmc.cnrs.fr/eDESIGN/index.html). Best twelve analogues were selected from a number designed analogues based on dock score and binding interactions. Further, the drug likeness properties were analyzed and found that all selected analogues have potential being antimalarial drug against cysteine protease falcipain-2. The root means square deviation (RMSD) and root means square fluctuation (RMSF) from the molecular dynamics simulation clearly indicated that selected analogues were formed stable complex with the cysteine protease falcipain2. The binding energy of all selected analogues was calculated using MM-GBSA approach and found that each molecule shown strong affinity towards the receptor cavity. Therefore, the outcome of the study undoubtedly substantiated that final analogues have potential to be promising inhibitors for the cysteine protease falcipain-2 and can be used for therapeutic application in malariaaffected people subjected to experimental validation.
Keywords : Cysteine proteases, Plasmodium falciparum, De novo design, molecular docking, molecular dynamics.