title: Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.
abstract: OBJECTIVE
  Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs.
  
  
  METHODS
  Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock.
  
  
  RESULTS
  The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having better binding affinity compared to the PDB bound inhibitor of falcipain-III. The docking simulation results of falcipain-III with designed leupeptin analogues using Glide compared with AutoDock and find 80% similarity as better binder than leupeptin.
  
  
  CONCLUSIONS
  These results further highlight new leupeptin analogues as promising future inhibitors for chemotherapeutic prevention of malaria. The result of Glide for falcipain-III has been compared with the result of AutoDock and finds very less differences in their order of binding affinity. Although there are no extra hydrogen bonds, however, equal number of hydrogen bonds with variable strength as compared to leupeptin along with the enhanced hydrophobic and electrostatic interactions in case of analogues supports our study that it holds the ligand molecules strongly within the receptor. The comparative e-pharmacophoric study also suggests and supports our predictions regarding the minimum features required in ligand molecule to behave as falcipain- III inhibitors and is also helpful in screening the large database as future antimalarial inhibitors.
authors.affiliation: Division of Applied Science and Indo-Russian Centre for Biotechnology, Indian Institute of Information Technology, Allahabad, India.
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Kesharwani
authors.forename: Durg Vijay
authors.initials: DV
authors.lastname: Singh
authors.forename: Krishna
authors.initials: K
authors.lastname: Misra
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007976:Leupeptins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects*; D011480:Protease Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000962:Antimalarials; D007976:Leupeptins; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases; C443101:falcipain 3; C032854:leupeptin