Journal of Enzyme Inhibition and Medicinal Chemistry Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone-chalcone and isatin-chalcone inhibitors probing the S2 active site pocket (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 ;
Journal of Chemical Information and Modeling, 2012
A new series of peptidomimetic pseudo-prolyl-homophenylalanylketones were designed, synthesized and evaluated for inhibition of the Plasmodium falciparum cysteine proteases falcipain-2 (FP-2) and falcipain-3 (FP-3). In addition, the parasite killing activity of these compounds in human blood-cultured P. falciparum was examined. Of twenty-two (22) compounds synthesized, one peptidomimetic comprising a homophenylalanine-based a-hydroxyketone linked Cbz-protected hydroxyproline (39) showed the most potency (IC 50 80 nM against FP-2 and 60 nM against FP-3). In silico analysis of these peptidomimetic analogs offered important protein-ligand structural insights including the role, by WaterMap, of water molecules in the active sites of these protease isoforms. The pseudo-dipeptide 39 and related compounds may serve as a promising direction forward in the design of competitive inhibitors of falcipains for the effective treatment of malaria.
Current Drug Targets, 2018
Background: The Plasmodium falciparum cysteine proteases, also known as falcipains, are involved in different erythrocytic cycle processes of the malaria parasite, e.g. hydrolysis of host haemoglobin, erythrocyte invasion, and erythrocyte rupture. With the biochemical characterization of four falcipains so far, FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases. They could therefore be referred to as potential anti-malarial drug targets in the search for novel therapies, which could ease the burden caused by the increasing resistance to current antimalarial drugs. Objectives: This review provides a summary of the most important results, highlighting the drug design approaches essential for the understanding of the mechanism of inhibition and discovery of inhibitors against cysteine proteases from P. falciparum. Results: Rational and computer-aided drug discovery approaches for the design of promising falcipain inhibitors are described herein, with a focus on a variety of structure-based and ligand-based modeling approaches. Moreover, the key features of ligand recognition against these targets are emphasized. Conclusion: This review would be of interest to scientists engaged in the development of drug design strategies to target the cysteine proteases, FP-2 and FP-3.
Computer-aided Design of Peptidomimetic Inhibitors of falcipain-3: QSAR and Pharmacophore Models
In this work antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) have been proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (IC50exp) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure-activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔGcomp) and the experimentally measured IC50exp: (pIC50exp=-(IC50exp/109) =-0.4517×∆∆Gcomp+4.0865 ; R2 = 0.89). Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogs where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed...
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...
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...
Structure-based design of parasitic protease inhibitors
Bioorganic & Medicinal Chemistry, 1996
To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compuo enzyme inhibitors including oxalic bis(2-hydroxy-l-naphthylmethylene)hydrazide [Ring, C. S.; Sun, E.; McKerow, J. H.; Lee, G.; Rosenthal, P. J., Kuntz, I. D.; Cohen, F. E., Proc. Natl Acad. Sci. U.S. A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC,~, 6 ~M) and the organism in vitro as judged by hypoxanthine uptake (ICs~, 7 ~tM). Following this lead, to date, we have identified potent bis arylacylhydrazides (ICs. 150 nM) and chalcones (IC~o 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 A., was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (ICso 600 ~tM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structurebased design program.
BioTechnologia, 2021
Despite significant progress made in drug discovery and development over the past few decades, malaria remains a life-threatening infectious disease across the globe. Because of the widespread emergence of drug-resistant strains of Plasmodium falciparum, the clinical utility of existing drug therapies including Artemisinin-based Combination Therapies (ACTs) in the treatment of malaria has been increasingly limited. It has become a serious health concern which, therefore, necessitates the development of novel drug molecules and/or alternative therapies to combat, particularly resistant P. falciparum. The objective of the present study was to develop 1,2,4-trioxane derivatives as novel antimalarial agents that would be effective against resistant P. falciparum. In our study, 15 new trioxane derivatives were designed by molecular modification of the 1,2,4-trioxane scaffold as possible antimalarial agents. Molecular modeling studies of trioxane derivatives were performed based on the CADD approach using Biovia Discovery Studio (DS) 2018 software. The protein-ligand docking study was performed against P. falciparum falcipain 2 (FP-2) using the simulation-based docking protocol LibDock by the flexible docking method. The assessment of drug-likeness, ADMET properties, and toxicity was also performed. Furthermore, the compounds CC3 and CC7, which showed the best binding affinity against the target P. falciparum FP-2, were investigated by molecular dynamics (MD) simulation studies followed by the calculation of MM-PBSA binding free energy of protein-ligand complexes using DS 2020. Results of the docking study showed that among the 15 compounds, three trioxane derivatives were found to possess promising binding affinity with LibDock scores ranging from 117.16 to 116.90. Drug-likeness, ADMET, and toxicity properties were found to be satisfactory for all the compounds. Among the 15 compounds, two compounds, namely CC3 and CC7, showed the highest binding affinity against FP-2 with LibDock score of 117.166 and 117.200, respectively. The Libdock score of the co-crystal inhibitor was 114.474. MD studies along with MM-PBSA calculations of binding energies further confirmed the antimalarial potential of the compounds CC3 and CC7, with the formation of well-defined and stable receptor-ligand interactions against the P. falciparum FP-2 enzyme. Additionally, the selectivity of trioxane hits identified as potential inhibitors of P. falciparum cysteine protease FP-2 was determined on human cysteine proteases such as cathepsins (Cat K and Cat L), which are host homologous. Finally, it was concluded that the newly designed 1,2,4trioxane derivatives can be further studied for in vitro and in vivo antimalarial activities for their possible development as potent antimalarial agents effective against resistant P. falciparum.
Anti-infective agents, 2012
In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structureactivity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q 2 and a non-cross-validation r 2 , which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC 50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors.