Targeting Cysteine Proteases from Plasmodium falciparum: A General Overview, Rational Drug Design and Computational Approaches for Drug Discovery (original) (raw)
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Journal of Analytical & Pharmaceutical Research
relationships; ΔΔG com , relative gibbs free energy change related to the enzyme-inhibitor complex formation; ΔΔH MM , relative enthalpic contribution to the Gibbs free energy change derived by molecular mechanics; ΔΔTS vib , relative entropic contribution of the inhibitor to the Gibbs free energy; ΔΔG sol , the relative solvation Gibbs free energy contribution to the gibbs free energy change; GFE, gibbs free energy; IC 50 exp , experimental inhibition constant ;
2019, VOL. 34, NO. 1, 547–561, 2019
We report computer-aided design of new lactone–chalcone and isatin–chalcone (HLCIC) inhibitors of the falcipain-2 (PfFP-2). 3D models of 15 FP-2:HLCIC1-15 complexes with known observed activity (IC50 exp) were prepared to establish a quantitative structure–activity (QSAR) model and linear correlation between relative Gibbs free energy of enzyme:inhibitor complex formation (DDGcom) and IC50 exp: pIC50 exp¼0.0236DDGcomþ5.082(#); R2¼0.93. A 3D pharmacophore model (PH4) derived from the QSAR directed our effort to design novel HLCIC analogues. During the design, an initial virtual library of 2621440 HLCIC was focused down to 18288 drug-like compounds and finally, PH4 screened to identify 81 promising compounds. Thirty-three others were added from an intuitive substitution approach intended to fill better the enzyme S2 pocket. One hundred and fourteen theoretical IC50 (IC50 pre) values were predicted by means of (#) and their pharmacokinetics (ADME) profiles. More than 30 putative HLCICs display IC50 pre 100 times superior to that of the published most active training set inhibitor HLCIC1.
Proceedings of the National Academy of Sciences, 2005
Falcipain-2 (FP2) is a papain family cysteine protease and important hemoglobinase of erythrocytic Plasmodium falciparum parasites. Inhibitors of FP2 block hemoglobin hydrolysis and parasite development, suggesting that this enzyme is a promising target for antimalarial chemotherapy. FP2 and related plasmodial cysteine proteases have an unusual 14-aa motif near the C terminus of the catalytic domain. Recent solution of the structure of FP2 showed this motif to form a -hairpin that is distant from the enzyme active site and protrudes out from the protein. To evaluate the function of this motif, we compared the activity of the wild-type enzyme with that of a mutant lacking 10 aa of the motif (⌬10 FP2). ⌬10 FP2 had nearly identical activity to that of the wild-type enzyme against peptide substrates and the protein substrates casein and gelatin. However, ⌬10 FP2 demonstrated negligible activity against hemoglobin or globin. FP2 that was inhibited with trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (FP2 E-64) formed a complex with hemoglobin, but ⌬10 FP2 E-64 did not, indicating that the motif mediates binding to hemoglobin independent of the active site. A peptide encoding the motif blocked hemoglobin hydrolysis, but not the hydrolysis of casein. Kinetics for the inhibition of ⌬10 FP2 were very similar to those for FP2 with peptidyl and protein inhibitors, but ⌬10 FP2 was poorly inhibited by the inhibitory prodomain of FP2. Our results indicate that FP2 utilizes an unusual motif for two specific functions, interaction with hemoglobin, its natural substrate, and interaction with the prodomain, its natural inhibitor. macromolecular interaction ͉ malaria ͉ drug discovery ͉ antimalarial chemotherapy
Structure-Function of Falcipains: Malarial Cysteine Proteases
2012
Evidence indicates that cysteine proteases play essential role in malaria parasites; therefore an obvious area of investigation is the inhibition of these enzymes to treat malaria. Studies with cysteine protease inhibitors and manipulating cysteine proteases genes have suggested a role for cysteine proteases in hemoglobin hydrolysis. The best characterized Plasmodium cysteine proteases are falcipains, which are papain family enzymes. Falcipain-2 and falcipain-3 are major hemoglobinases of P. falciparum. Structural and functional analysis of falcipains showed that they have unique domains including a refolding domain and a hemoglobin binding domain. Overall, the complexes of falcipain-2 and falcipain-3 with small and macromolecular inhibitors provide structural insight to facilitate the design or modification of effective drug treatment against malaria. Drug development targeting falcipains should be aided by a strong foundation of biochemical and structural studies.
Universal Journal of Pharmaceutical Research
Aim and Objective: Structure-based drug design (SBDD) of new antimalarials at the moment of resistance of the most causative agent, Plasmodium falciparum to the more valuable artemisinin combination therapy (ACT) is even more urgent. Carbonitriles pyrimidine derivatives (CNP) has emerged as potential inhibitors of the cysteine protease falcipain 2 of Plasmodium falciparum (pfFP2), so here we report virtual pharmacophore based screening of the CNP chemical subspace yielding novel CNP analogs with predicted high inhibitory potency against pfFP2. Methods: A quantitative structure activity relationships (QSAR) complexation model has been developed from a series of fifteen carbonitriles pyrimidine derivatives to establish a linear correlation between the calculated Gibbs free energies (GFE: ΔΔGcom) of pfFP2-CNP complex formation and the experimental half-maximal enzymatic inhibition concentration ( ).The predictive power of the QSAR model was then validated with the generation of a 3D-QS...
Journal of vector borne diseases
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. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate...
Journal of Medicinal Chemistry, 2008
Falcipain-2 (FP-2), a papain family cysteine protease of Plasmodium falciparum, is a promising target for antimalarial chemotherapy. Designing inhibitors that are highly selective for falcipain-2 has been difficult because of broad specificity of different cysteine proteinases. Because propeptide regions of cysteine proteases have been shown to inhibit their cognate enzymes specifically and selectively, in the present study, we evaluated the inhibitory potential of few falcipain-2 proregion peptides. A 15 residue peptide (PP1) inhibited falcipain-2 enzyme activity in vitro. Studies on the uptake of PP1 into the parasitized erythrocytes showed access of peptide into the infected RBCs. PP1 fused with Antennapedia homeoprotein internalization domain blocked hemoglobin hydrolysis, merozoite release and markedly inhibited Plasmodium falciparum growth and maturation. Together, our results identify a peptide derived from the proregion of falcipain-2 that blocks late-stage malaria parasite development in RBCs, suggesting the development of peptide and peptidometric drugs against the human malaria parasite.
Journal of Medicinal Chemistry, 2008
Falcipain-2 (FP-2), a papain family cysteine protease of Plasmodium falciparum, is a promising target for antimalarial chemotherapy. Designing inhibitors that are highly selective for falcipain-2 has been difficult because of broad specificity of different cysteine proteinases. Because propeptide regions of cysteine proteases have been shown to inhibit their cognate enzymes specifically and selectively, in the present study, we evaluated the inhibitory potential of few falcipain-2 proregion peptides. A 15 residue peptide (PP1) inhibited falcipain-2 enzyme activity in vitro. Studies on the uptake of PP1 into the parasitized erythrocytes showed access of peptide into the infected RBCs. PP1 fused with Antennapedia homeoprotein internalization domain blocked hemoglobin hydrolysis, merozoite release and markedly inhibited Plasmodium falciparum growth and maturation. Together, our results identify a peptide derived from the proregion of falcipain-2 that blocks late-stage malaria parasite development in RBCs, suggesting the development of peptide and peptidometric drugs against the human malaria parasite.
Structure- and function-based design of Plasmodium-selective proteasome inhibitors
Nature, 2016
The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome...