Plasmepsin Inhibitors Research Articles

Antimalarial Activities of a Therapeutic Combination of Azadirachta indica, Mangifera indica and Morinda lucida Leaves: A Molecular View of its Activity on Plasmodium falciparum Proteins.

The search for new antimalarial drugs remains elusive prompting research into antimalarial combinations from medicinal plants due to their cheapness, efficacy and availability. Azadirachta indica (AI), Morinda lucida (ML) and Mangifera indica (MI) have all been reported as potent antimalarial plants. This study evaluated the efficacy of an antimalarial combination therapeutics prepared from leaves of AI, ML and MI using in vitro, in vivo and molecular methods. Refined extracts of the plants combination was made by partitioning the aqueous extract of plants combinations (AI + MI, AI + ML, MI + ML, AI + MI + ML) using methanol and ethyl acetate consecutively. The resulting ethyl acetate partitioned fraction was evaluated for its antimalarial activity. Molecular docking and molecular dynamics simulation were employed to determine the possible mechanism of action of the constituent of the most active combination against four important P. falciparum proteins. The result revealed that the refined extract from combinations AI + ML and MI + ML at 16mg/kg bodyweight have the highest chemo-suppressive effect of 90.7% and 91.0% respectively compared to chloroquine's 100% at 10mg/kg. Also, refined extract from MI + ML combination improved PCV levels significantly (p < 0.05) compared to controls. Molecular docking revealed oleanolic acid and ursolic acid as multiple inhibitors of plasmepsin II, hiso-aspartic protease, falcipain-2 and P. falciparum Eonyl acyl-carrier protein reductase with relative stability during 100ns of simulation. The study unveiled the potentials of ML and MI as good candidates for antimalarial combination therapy and further established their use together as revealed in folklore medicine.

Bridging the Gap in Malaria Parasite Resistance, Current Interventions, and the Way Forward from in Silico Perspective: A Review.

The past decade has seen most antimalarial drugs lose their clinical potency stemming from parasite resistance. Despite immense efforts by researchers to mitigate this global scourge, a breakthrough is yet to be achieved, as most current malaria chemotherapies suffer the same fate. Though the etiology of parasite resistance is not well understood, the parasite's complex life has been implicated. A drug-combination therapy with artemisinin as the central drug, artemisinin-based combination therapy (ACT), is currently the preferred malaria chemotherapy in most endemic zones. The emerging concern of parasite resistance to artemisinin, however, has compromised this treatment paradigm. Membrane-bound Ca2+-transporting ATPase and endocytosis pathway protein, Kelch13, among others, are identified as drivers in plasmodium parasite resistance to artemisinin. To mitigate parasite resistance to current chemotherapy, computer-aided drug design (CADD) techniques have been employed in the discovery of novel drug targets and the development of small molecule inhibitors to provide an intriguing alternative for malaria treatment. The evolution of plasmepsins, a class of aspartyl acid proteases, has gained tremendous attention in drug discovery, especially the non-food vacuole. They are expressed at multi-stage of the parasite's life cycle and involve in hepatocytes' egress, invasion, and dissemination of the parasite within the human host, further highlighting their essentiality. In silico exploration of non-food vacuole plasmepsin, PMIX and PMX unearthed the dual enzymatic inhibitory mechanism of the WM382 and 49c, novel plasmepsin inhibitors presently spearheading the search for potent antimalarial. These inhibitors impose structural compactness on the protease, distorting the characteristic twist motion. Pharmacophore modeling and structure activity of these compounds led to the generation of hits with better affinity and inhibitory prowess towards PMIX and PMX. Despite these headways, the major obstacle in targeting PM is the structural homogeneity among its members and to human Cathepsin D. The incorporation of CADD techniques described in the study at early stages of drug discovery could help in selective inhibition to augment malaria chemotherapy.

Disrupting the characteristic twist motion; tailored in silico approach towards the design of plasmepsin inhibitors

The effort to eradicate malaria has not yet been achieved, and the parasitic infection remains a global challenge. The burden stems from the worldwide dissemination of parasites resistant to commonly used chemotherapeutics and the scarcity of the malaria vaccine, Mosquirix. In the quest to augment malaria treatment, current focus has been geared towards plasmepsin (P). These classes of aspartic acid proteases are expressed at multiple stages of the parasite's life cycle and are implicated in host haemoglobin degradation and parasite dissemination in vivo; elaborating their essentiality as therapeutic targets. Our earlier research examined the structural dynamics of WM382, a novel antimalarial compound, in relation to its enzyme inhibitory mechanism on plasmepsin IX (PMIX) and plasmepsin X (PMX). WM382 inflicts structural compactness on both proteases. The pharmacophoric moieties of WM382 were used in the present study to search the Zinc database for WM382 derivatives. The leads, ZINC06868602, ZINC09431717 and ZINC13367223 formed strong intermolecular bonds with the catalytic dyad Asp32 and Asp281. The flap regions generally move away from the binding pocket, divulging the active site to the inhibitor and keeping it near to the catalytic dyad. However, upon binding of the leads, the flap residues wrapped inward to surround the inhibitors, further restricting the characteristic twist motion of these proteases for enzyme activity. Likewise, for the experimental drug candidate WM382, the identified leads displayed high affinity for PMIX, with total binding free energies of leads estimated to be −33.45 kcal/mol, −30.33 kcal/mol and −29.67 kcal/mol, respectively. Evaluation of per residue energy composition indicated the catalytic dyad contributes immensely towards ligand binding. Results from our study suggest these compounds have better inhibitory prowess against PMIX. The potency of these chemicals should further be tested in the experimental laboratory to evaluate their usefulness.

In silico validation of novel inhibitors of malarial aspartyl protease, plasmepsin V and antimalarial efficacy prediction

Plasmepsin V (Plm V) is an essential aspartic protease required for survival of the malaria parasite, Plasmodium falciparum (Pf). Plm V is required for cleaving the PEXEL motifs of many Pf proteins and its inhibition leads to a knockout effect, indicating its suitability as potential drug target. To decipher new inhibitors of PfPlm V, molecular docking of four HIV-1 protease inhibitors active against PfPlmV was performed on Glide module of Schrödinger suite that supported saquinavir as a lead drug, and therefore, selected as a control. Saquinavir contains an important hydroxyethylamine (HEA) pharmacophore, which was utilized as backbone coupled with piperazine scaffold to build new library of compounds. Newly designed HEA compounds were screened virtually against Plm V. Molecular docking led to a few hits (1 and 3) with higher docking score over the control drug. Notably, compound 1 showed the highest docking score (–11.90 kcal/mol) and XP Gscore (–11.948 kcal/mol). The Prime MMGBSA binding free energy for compound 1 (–60.88 kcal/mol) and 3 (–50.96 kcal/mol) was higher than saquinavir (–37.51 kcal/mol). The binding free energy for the last frame of molecular dynamic simulation supported compound 1 (–92.88 kcal/mol) as potent inhibitor of PfPlm V over saquinavir (–72.77 kcal/mol), and thus, deserves experimental validations in culture and subsequently in animal models. Communicated by Ramaswamy H. Sarma

In Silico Docking, ADMET and QSAR Study of few Antimalarial Phytoconstituents as Inhibitors of Plasmepsin II of P. falciparum Against Malaria

Background: Malaria is endemic in various parts of India particularly in the North- Eastern states with Plasmodium falciparum-the most prevalent human malaria parasite. Plantderived compounds have always received tremendous importance in the area of drug discovery and development and scientific study of traditional medicinal plants are of great importance to mankind. Objective: The present work deals with the computational study of some antimalarial compounds obtained from a few medicinal plants used by the tribal inhabitants of the North-Eastern region of India for treating malaria. Methods: In silico methodologies were performed to study the ligand-receptor interactions. Target was identified based on the pharmacophore mapping approach. A total of 18 plant-derived compounds were investigated in order to estimate the binding energies of the compounds with their drug target through molecular docking using Autodock 4.2. ADMET filtering for determining the pharmacokinetic properties of the compounds was done using Mobyle@RPBS server. Subsequent Quantitative-Structure Activity Relationship analysis for bioactivity prediction (IC50) of the compounds was done using Easy QSAR 1.0. Results: The docking result identified Salannin to be the most potent Plasmepsin II inhibitor while the QSAR analysis identified Lupeol to have the least IC50 value. Most of the compounds have passed the ADME/Tox filtration. Conclusion: Salannin and Lupeol were found to be the most potent antimalarial compounds that can act as successful inhibitors against Plasmepsin II of P. falciparum. The compounds Salannin and Lupeol are found in Azadirachta indica and Swertia chirata plants respectively, abundantly available in the North-Eastern region of India and used by many inhabiting tribes for the treatment of malaria and its symptoms.

Click Inspired Synthesis of Novel Cinchonidine Glycoconjugates as Promising Plasmepsin Inhibitors

Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins.

Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present).

Plasmepsins represent novel antimalarial drug targets. However, plasmepsin-based antimalarial drug discovery efforts in the past 2 decades have generally suffered some drawbacks including lack of translatability of target inhibition to potent parasite inhibition in vitro and in vivo as well as poor selectivity over the related human aspartic proteases. Most studies reported in this period have over-relied on the use of hemoglobinase plasmepsins I-IV (particularly I and II) as targets for the new inhibitors even though these are known to be nonessential at the asexual stage of parasite development. Therefore, future antimalarial drug discovery efforts seeking to identify plasmepsin inhibitors should focus on incorporating non-hemoglobinase plasmepsins such as V, IX, and X in their screening in order to maximize chances of success. Additionally, there is need to go beyond just target enzymatic activity profiling to establishing cellular activity, physicochemical as well as drug metabolism and pharmacokinetics properties and finally in vivo proof-of-concept while ensuring selectivity over related human host proteases.

Antimalarial Phytochemicals Identification from Euphorbia Hirta against Plasmepsin Protease: an In Silico Approach.

Aspartic protease found in plasmodium parasites such as plasmepsin I, II and IV plays an important role in the degradation of hemoglobin. The studies have shown that effective drug must be able to inhibit more than one type of plasmepsin to avoid further growth of parasites and to prevent resistance of drug. Therefore, plasmepsins are believed to be excellent drug target for malarial disease. Extract of the plant Euphorbia hirta has been proved to exert antimalarial activity. However, molecular mechanism of this activity was not described. The aim of present investigation is to identify antimalarial phytochemicals of Euphorbia hirta as plasmepsin protease inhibitors using an in silico approach. Docking studies were performed on three different protein targets plasmepsin I, II, and IV using iGEMDOCK. ADME and bioactivity predictions were done using molinspiration online tool. Toxicity studies were performed using ProTox-II online tool. In the docking studies seven compounds showed significant inhibitory activity with low docking score as compared to standard drug artemisinin. Six compounds showed no violations as per Lipinski rule. Bioactivity prediction states that all the compounds may act through enzyme inhibition. The results of in silico studies suggest that out of the eleven selected phytochemicals isorhamnetin and pinocembrin have more drug likeliness properties and lesser in silico toxicity with more binding affinity than artemisinin on all receptors. These findings indicate that isorhamnetin and pinocembrin have promising potential for development of antimalarial drug as plasmepsin inhibitors.

Unveiling a New Era in Malaria Therapeutics: A Tailored Molecular Approach Towards the Design of Plasmepsin IX Inhibitors.

The invasive tactics employed by the malarial parasite renders malaria a global health threat, further impeding the effective treatment of the mosquito borne-parasitic disease. Although there have been countless efforts directed towards the development of effective therapeutics, factors such as emerging strains of drug resistance, enhanced toxicity and poor pharmacokinetic properties of current therapeutics has hampered the drug discovery process resulting in the spread of this parasitic disease. A promising target of the most lethal strain of the Plasmodium species that plays a predicted role in erythrocyte invasion of the virulent malarial parasite is aspartic protease IX commonly referred to Plasmepsin IX. The integration of computer aided-drug design platforms has revolutionized the 21st century and has opened avenues to render a final "knock out" in the elimination and eradication of this parasitic disease Hitherto, this is the first attempt directed towards the design of therapeutics tailored explicitly to Plasmepsin IX. A potent peptidomimetic inhibitor referred to as 49c which is a known inhibitor of Plasmepsin II, has recently exhibited potent inhibitory activity against Plasmepsin IX. In-silico structural and physicochemical inspection of 49c displayed poor pharmacokinetic properties thus paving the way for the development of tailored inhibitors with desirable therapeutic properties against Plasmepsin IX. In this study we implement the pharmacophore model approach in combination with per-residue energy decomposition analysis to serve as a powerful cornerstone, that may assist medicinal experts in the composition of multifunctional therapeutics that may predispose factors such as cross-resistance and toxicity, with enhanced pharmacokinetic properties.

Exploiting Structural Dynamics To Design Open-Flap Inhibitors of Malarial Aspartic Proteases.

Malaria is a life-threatening infectious disease caused by Plasmodium parasites. Plasmepsins (proteolytic enzymes of the parasite) have been considered as promising targets for the development of antimalarial drugs. To date, much knowledge has been obtained regarding the interactions of inhibitors with plasmepsins, as well as the structure-activity relationships of the inhibitors. The discovery and characterization of the plasmepsin inhibitors that bind in open flap conformation have led to several inhibitor classes that show high selectivity over other human aspartic proteases. This Perspective addresses the flexibility of the plasmepsins that leads to inhibitor binding to the open flap conformation, summarizes known nonpeptidomimetic plasmepsin inhibitors, and discusses the role of the inhibitor flap pocket substituent.

Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions.

Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.

Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D

Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P. falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.

Targeting the Plasmodium falciparum plasmepsin V by ligand‐based virtual screening

Malaria is a devastating disease depending only on chemotherapy as treatment. However, medication is losing efficacy, and therefore, there is an urgent need for the discovery of novel pharmaceutics. Recently, plasmepsin V, an aspartic protease anchored in the endoplasmaic reticulum, was demonstrated as responsible for the trafficking of parasite-derived proteins to the erythrocytic surface and further validated as a drug target. In this sense, ligand-based virtual screening has been applied to design inhibitors that target plasmepsin V of P. falciparum (PMV). After screening 5.5 million compounds, four novel plasmepsin inhibitors have been identified which were subsequently analyzed for the potency at the cellular level. Since PMV is membrane-anchored, the verification in vivo by using transgenic PMV overexpressing P. falciparum cells has been performed in order to evaluate drug efficacy. Two lead compounds, revealing IC50 values were 44.2 and 19.1μm, have been identified targeting plasmepsin V invivo and do not significantly affect the cell viability of human cells up to 300μm. We herein report the use of the consensus of individual virtual screening as a new technique to design new ligands, and we propose two new lead compounds as novel protease inhibitors to target malaria.

Azole-based non-peptidomimetic plasmepsin inhibitors.

The spread of drug-resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases - plasmepsins (Plms) - are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole-based non-peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino-piperazine inhibitors. The best triazole-based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance-free antimalarial drug targeting the non-digestive Plm IX or X, which are essential for the malaria parasite life cycle.

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 ± 0.29 µM for Plm II; Ki, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 ± 0.95 µM for 10f; IC50, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.

Plerixafor and related macrocyclic amines are potential drug candidates in treatment of malaria by “filling the flap” region of plasmepsin enzymes

Death by Plasmodium falsiparum, the leading cause of malaria, is going to remain a major obstacle among the infectious diseases. Plasmepsin aspartic proteases are key proteins in the pathogenesis of plasmodium species which break down the hemoglobin and exploit it as a source of amino acids. These enzymes are one of the favorite targeting agents for medicinal chemists to design new drugs. Plasmepsin proteins show a “flap” region in their N-terminal domain, predisposing them to a good “filler” drug with an exceptional affinity to this enzyme. Plerixafor (Mozobil®, AMD3100), a CXCR4 antagonist with a bicyclam ring, historically discovered as an impurity in a mixture which had anti-HIV properties, is now a FDA approved drug for mobilizing haematopoietic stem cells in cancer patients. In this hypothesis, we focused on the similarity of the structure of plerixafor and its analogues with heme functional group of hemoglobin, the main substrate of plasmepsin, and also with some other recent azamacrocyclic compounds demonstrating antimalarial activity, to test whether these compounds are capable of exhibiting antimalarial activity by inhibiting plasmepsin or not. A preliminary in silico docking study was used to evaluate this hypothesis and docking results indicated that macrocyclic cyclams and cyclens can reliably act as potent lead drug or central pharmacophore in developing new plasmepsin inhibitors as compared with previously designed plasmepsin II inhibitors.

Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P2 position of PEXEL peptidomimetics

Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P3 Arg and P1 Leu in binding affinity and selectivity. Here, we investigate the importance of the P2 position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylglycine or phenylglycine in the P2 position are the most potent inhibitors of plasmepsin V that impair processing of the PEXEL motif in exported proteins resulting in death of P. falciparum asexual stage parasites.

2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity

2-Aminoquinazolin-4(3H)-ones were previously discovered as perspective leads for antimalarial drug development targeting the plasmepsins. Here we report the lead optimization studies with the aim to reduce inhibitor lipophilicity and increase selectivity versus the human aspartic protease Cathepsin D. Exploiting the solvent exposed area of the enzyme provides an option to install polar groups (R1) the 5-position of 2-aminoquinazolin-4(3H)-one to inhibitors such as carboxylic acid without scarifying enzymatic potency. Moreover, introduction of R1 substituents increased selectivity factors of compounds in this series up to 100-fold for Plm II, IV vs CatD inhibition. The introduction of flap pocket substituent (R2) at 7-postion of 2-aminoquinazolin-4(3H)-one allows to remove Ph group from THF ring without notably impairing Plm inhibitory potency. Based on these findings, inhibitors were developed, which show Plm II and IV inhibitory potency in low nanomolar range and remarkable selectivity against Cathepsin D along with decreased lipophilicity and increased solubility.

Multiple target-based pharmacophore design from active site structures

Health care systems have benefitted from rational drug discovery processes like vHTS, virtual high throughput screening pharmacophores and quantitative structure–activity relationships, and many challenges have been explored using such techniques: decisions on specificity and selectivity are made after screening millions of molecules for multiple targets. Recent challenges in drug research emphasize the design of drugs that bind with more than one target of interest (multi-target) and do not bind with undesirable targets. This work attempts to use a three-dimensional interaction profile of the active site of a class of proteins, identify selective positions for the binding of functional groups, called features, and develop ensembles of multi-targeted pharmacophores that retain specificity and selectivity. The goal of this study is to develop multi-target pharmacophores by computational methods using protein structures alone to guide the discovery of novel inhibitors of plasmepsins, displaying selectivity over their human homologs, cathepsin D and pepsin. The development of such novel tools is attempted using a combination of different approaches such as the molecular interaction field, clique graph and inductive logic programming to identify and compare specific and selective complementary features. The identification of selective combinations of features has resulted in the design of multi-featured specific and selective pharmacophores that are validated using antimalarial compounds in ChEMBL that are known for their anti-plasmepsin II activity. This novel method is computationally less intensive and is applicable to any known class of target structures for finding specific and selective binders simultaneously.

In-silico Antimalarial Study of Monocarbonyl Curcumin Analogs and Their 2,4-Dinitro Phenylhydrazones Using the Inhibition of Plasmepsin II as Test Model

A well-known component of the Indian spice turmeric, curcumin, has received a lot of attention in recent years as a potential antimalarial agent but the inherent problems associated with low bioavailabilty tends to limit its applicability. The bioavailability is linked to its low solubility in water and its rapid break down in the blood plasma. In this study, we have proposed the use of synthetic analogs of curcumin and their derivatives which are expected to be less prone to degradation in the blood plasma as possible antimalarials. The binding affinity of monocarbonyl analogs of curcumin and their 2,4-dinitrophenylhydrazone derivatives for the chain A domain of plasmepsin II, one of the key enzymes involved in hemoglobin digestion in the food vacuole of the malaria parasite was determined by computational docking analysis, performed using Auto Dock Vina 1.1.2, pymol and Chem 3D ultra 12.0. The binding energies of the 20 compounds studied was compared with that of pepstatin A (a known inhibitor of plasmepsin II), curcumin and chloroquine. The 3D structure of the protein was obtained from the protein data bank (PDB ID:1M43), the compounds’ 3D structure was generated with the Chem 3D ultra 12.0 and visualization done with pymol. Out of the 20 compounds docked with plasmepsin II, 17 had binding energies higher than that of pep A (-32.6, kJ/mol) and 19 of the compounds had binding energies higher than that of curcumin (30.96, kJ/mol). The docked compounds, 5b, 6b and 7b had the highest binding energies (-44.73 kJ/mol, -42.64 kJ/mol and -41.80 kJ/mol respectively). It is expected that the compounds with binding energies higher than that of pep A may be considered for further antimalarial studies in-vitro and in-vivo.