title: Probing the structure of falcipain-3, a cysteine protease from Plasmodium falciparum: comparative protein modeling and docking studies.
abstract: Increasing resistance of malaria parasites to conventional antimalarial drugs is an important factor contributing to the persistence of the disease as a major health threat. The ongoing search for novel targets has resulted in identification and expression of several enzymes including cysteine proteases that are implicated in hemoglobin degradation. Falcipain-2 and falcipain-3 are considered to be the two principal cysteine proteases in this degradation, and hence, are potential drug targets. A homology model of falcipain-3 was built and validated by various structure/geometry verification tools as well as docking studies of known substrates. The correlation coefficient of 0.975 between interaction energies and K(m) values of these substrates provided additional support for the model. On comparison with the previously reported falcipain-2 homology model, the currently constructed falcipain-3 structure showed important differences between the S2 pockets that might explain the variations in the K(m) values of various substrates for these enzymes. Further, docking studies also provided insight into possible binding modes and interactions of ligands with falcipain-3. Results of the current study could be employed in de novo drug design leading to development of new antimalarial agents.
authors.affiliation: Department of Medicinal Chemistry, National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, Mississippi 38677-1848, USA.
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Sabnis
authors.forename: Prashant V
authors.initials: PV
authors.lastname: Desai
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D039301:Computers, Molecular; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000254:growth & development; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D003546:Cysteine Endopeptidases; C443101:falcipain 3