Falciparum Dihydroorotate Dehydrogenase Research Articles

In vitro antiplasmodium and antitrypanosomal activities, β-haematin formation inhibition, molecular docking and DFT computational studies of quinoline-urea-benzothiazole hybrids

Quinoline-urea-benzothiazole hybrids exhibited low to sub-micromolar in vitro activities against the Plasmodium falciparum (P. falciparum) 3D7 chloroquine (CQ)-sensitive strain, with compounds 5a, 5b and 5f showing activities ranging from 0.33 to 0.97 μM. Against the formation of β-haematin, the majority of the tested compounds were comparable to the reference drug, chloroquine (CQ), with compounds 5c (IC50 = 9.55 ± 0.62 μM) and 5h (IC50 = 9.73 ± 1.38 μM), exhibiting slightly better in vitro efficacy than CQ. The hybrids also exhibited low micromolar to submicromolar activities against Trypanosoma brucei brucei, with 5j-5k being comparable to the reference drug, pentamidine. Compound 5b displayed higher in silico binding energy than CQ when docked against P. falciparum dihydroorotate dehydrogenase enzyme. Compounds 5j and 5k showed higher binding energies than pentamidine within the trypanothione reductase enzyme binding pocket. The root means square deviations of the hit compounds 5b, 5j and 5k were stable throughout the 100 ns simulation period. Post-molecular dynamics MMGBSA binding free energies showed that the selected hybrids bind spontaneously to the respective enzymes. The DFT investigation revealed that the compounds have regions that can bind to the electropositive and electronegative sites of the proteins.

Kajian Farmakoinformatika Senyawa Caulerchlorin dan Racemosin sebagai kandidat Antimalaria

Caulerchlorin and racemosin were bioactive compounds containing in Caulerpa racemosa macroalgae. Previous study, those compounds promoted therapeutical target on metabolic syndrome. However, the therapeutical activity on Malaria not yet defined. Therefore, this study investigated potential activity of caulerchlorin and racemosin from Caulerpa racemosa as antimalarial activity through pharmacoinformatic study. Caulerchlorin and racemosin structures were retrieved from PubChem NCBI and the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) structure was taken out from Protein database with ID 5GJG. Orotic acid was used as native ligand or control. Ligands were predicted their antiplasmodial activity and toxicity. Ligands and protein were interacted by redocking using Molegro Virtual Docker version 6.0 and analyzed by using PyMol 2.3 and Discovery Studio version 21.1.1. Two bioactive compounds also showed antiplasmodial activity and were not mutagenicity and hepatotoxicity affections. Molecular docking performed that caulerchlorin and racemosin exhibited same active residues as well as orotic acid as native substrate. Binding energy revealed two compounds, caulerchlorin and racemosin showed lower binding energy than orotic acid. In summary caulerchlorin and racemosin were potentially inhibited PfDHODH activity by binding substrate sites of PfDHODH protein.

In-silico studies of hydroxyxanthone derivatives as potential pfDHFR and pfDHODH inhibitor by molecular docking, molecular dynamics simulation, MM-PBSA calculation and pharmacokinetics prediction

The investigation of hydroxyxanthone derivatives has been conducted, including molecular docking, molecular dynamics simulation MM-PBSA binding energy calculation, and pharmacokinetics prediction of the potential plasmodium falciparum dihydrofolate reductase (pfDHFR) and plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH) inhibitor. The Docking result showed that compound 1,3,6,7-tetrahydroxy-5,8-bis(3-methyl-2-buten-1-yl)-9H-xanthen-9-one (X16) was found to be the best ligand with good inhibitory action against pfDHFR. Meanwhile, the pfDHODH protein was compounded 1,3,6,7-tetrahydroxy-5,8-dinitro-9H-xanthen-9-one (X14). Additionally, the hydroxyxanthone X16 complex showed more excellent stability in the molecular dynamics simulation of the pfDHFR protein than the ligand WR99210 and chloroquine. The MM-PBSA calculation showed that compound X16 had lower binding energy than ligand WR99210. However, 1,3-dihydroxy-8-(3-methyl-2-buten-1-yl)-9H-xanthen-9-one (X4), 1,3,6,7-tetrahydroxy-8-nitro-9H-xanthen-9-one (X10), 1,3,6,7-tetrahydroxy-9-oxo-9H-xanthene-8-sulfonic acid (X11), and 1,3,6,7-tetrahydroxy-5,8-dinitro-9H-xanthen-9-one (X14) complexes were shown to be more stable than chloroquine and to have the same stability when compared to the native ligand A26, according to a molecular dynamics simulation conducted in pfDHODH protein. The MM-PBSA calculation showed that compound X14 had lower binding energy than ligand A26. The hydroxyxanthones X4, X10–11, X14, and X16 fulfill Lipinski's rule parameters in terms of physicochemical and ADMET qualities and parameters related to absorption, distribution, metabolism, excretion, and toxicity tests. To sum up, hydroxyxanthones X4, X10–11, X14, and X16 have the potential to be antimalarial medications, but more in vivo and in vitro testing is needed to confirm this.

Repurposing of Drug Bank Compounds against Plasmodium falciparum Dihydroorotate Dehydrogenase as novel anti malarial drug candidates by Computational approaches.

Repurposing of Drug Bank Compounds against Plasmodium falciparum Dihydroorotate Dehydrogenase as novel anti malarial drug candidates by Computational approaches.

Microencapsulation, Physicochemical Characterization, and Antioxidant, Antibacterial, and Antiplasmodial Activities of Holothuria atra Microcapsule

This study provides the design of a microencapsulation formula, physicochemical characterization, and antioxidant, antibacterial, and antiplasmodial activities of Holothuria atra microcapsules. The ethanolic extract of H. atra was microencapsulated with chitosan (CHI) and sodium tripolyphosphate (Na‐TPP) with various stirring times: 60 minutes (CHI60), 90 minutes (CHI90), and 120 minutes (CHI120). The microcapsules were then observed for physicochemical properties using scanning electron microscopy (SEM) and Fourier‐transform infrared spectroscopy (FTIR). The microcapsules were tested for antioxidant activity and antibacterial activity against Staphylococcus aureus and Escherichia coli using the DPPH (2,2‐diphenyl‐1‐picrylhydrazyl) method. Antiplasmodial bioactivity was assessed through in silico molecular docking. The CHI60 and CHI120 microcapsules exhibited a smaller size and an irregular spherical shape, while the same FTIR profile was observed in CHI90 and CHI120. The bioactivity tests demonstrated that CHI90 exhibited high antibacterial activity against E. coli and S. aureus, while CHI120 exhibited high antioxidant performance. Calcigeroside B and Echinoside B exhibited antiplasmodial activity against the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) protein, along with an artemisinin inhibition mechanism. In conclusion, the microcapsules with the CHI90 formula demonstrated the best antibacterial activity, while the CHI120 formula exhibited high antioxidant activity. Two terpenoids, Calcigeroside B and Echinoside B, exhibited the best antiplasmodial activity.

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective.

Malaria is a parasitic disease that, in its most severe form, can even lead to death. Insect-resistant vectors, insufficiently effective vaccines, and drugs that cannot stop parasitic infestations are making the fight against the disease increasingly difficult. It is known that the enzyme dihydroorotate dehydrogenase (DHODH) is of paramount importance for the synthesis of pyrimidine from the Plasmodium precursor, that is, for its growth and reproduction. Therefore, its blockade can lead to disruption of the parasite's life cycle in the vertebrate host. In this scenario, PfDHODH inhibitors have been considered candidates for a new therapy to stop the parasitic energy source. Given what is known, in this work, we applied molecular fractionation with conjugated caps (MFCC) in the framework of the quantum formalism of density functional theory (DFT) to evaluate the energies of the interactions between the enzyme and the different triazolopyrimidines (DSM483, DMS557, and DSM1), including a complex carrying the mutation C276F. From these results, it was possible to identify the main features of each system, focusing on the wild-type and mutant PfDHODH and examining the major amino acid residues that are part of the four complexes. Our analysis provides new information that can be used to develop new drugs that could prove to be more effective alternatives to present antimalarial drugs.

In vitro antiplasmodial activity, LC-MS analysis, and molecular docking studies of bioactive compounds from Tetrapleura tetraptera (Fabaceae) fruits

Malaria continues to be a major public health concern, particularly for children and pregnant women in areas where the disease is endemic. Developing safe and efficient antimalarial therapies to fight the disease is essential. Medicinal plants represent a potential source for the development of new antimalarial drugs. Tetrapleura tetraptera is a plant native to West Africa and traditionally used to treat several diseases including Malaria. Here, we investigated the antiplasmodial activities of T. tetraptera fruit extracts against the chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfDD2) strains of Plasmodium falciparum in vitro using SYBR green assay. In addition, the antioxidant potential of the fruit extracts was also determined. LC-MS analysis was carried out to identify the bioactive compounds in the extracts. Molecular docking studies provide significant prima facie evidence of inhibition hence, to evaluate the potential inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a validated malaria drug target, the identified compounds were docked against PfDHODH. Strong antiplasmodial activities were demonstrated by the ethyl acetate and ethanolic extracts of T. tetraptera fruit, with IC50 values of 16.12 ± 0.04 µg/mL and 2.06 ± 0.02 µg/mL against the Pf3D7 strain, respectively. In the DPPH radical scavenging experiment, the ethanolic extract revealed considerable antioxidant activity with an EC50 value of 0.21 ± 0.82 mg/mL. Seven bioactive compounds were identified in the extract using LC-MS analysis. N-Methyl-1H-indole-3-propanamide (I), Tazolol (II), and Isopentyl salicylate (III) were identified as potential inhibitors of PfDHODH with high binding affinities ranging from -32.08 to -30.69 kcal/mol. The potential lead compounds also interacted with Gly181, Leu531, and Arg265, which are critical amino acid residues in the catalytic activity of PfDHODH. These findings support the traditional use of T. tetraptera fruit extracts for the treatment of malaria and as promising avenues for antimalarial drug development.

Parasitic Protozoans: Exploring the Potential of N,N'-Bis[2-(5-bromo-7-azabenzimidazol-1-yl)-2-oxoethyl]ethylene-1,3-Diamine and Its Cyclohexyl-1,2-diamine Analogue as TryR and Pf-DHODH Inhibitors.

Major human parasitic protozoans, such as Plasmodium falciparum and Trypanosoma brucei, cause malaria and trypanosomiasis also known as sleeping sickness. In anti-parasitic drug discovery research, trypanothione reductase (TryR) and P. falciparum dihydroorotate dehydrogenase (Pf-DHODH) enzymes are key drug targets in T. brucei and P. falciparum, respectively. The possibility of co-infection of single host by T. brucei and P. falciparum is because both parasites exist in sub-Saharan Africa and the problem of parasite drug resistance necessitates the discovery of new scaffolds, which are strange to the organisms causing these infectious diseases-new scaffolds may help overcome established resistance mechanisms of the organisms. In this study, N,N'-bis[2-(5-bromo-7-azabenzimidazol-1-yl)-2-oxoethyl]ethylene-1,3-diamine and its cyclohexyl-1,2-diamine analogue were explored for their inhibitory potential against TryR and Pf-DHODH by engaging density functional study, molecular dynamic simulations, drug-likeness, in silico and in vitro studies RESULTS/CONCLUSION: Results obtained indicated excellent binding potential of the ligands to the receptors and good ADMET (adsorption, desorption, metabolism, excretion, and toxicity) properties.

Design, synthesis, and in silico studies of benzimidazoles of thymol as potent antiplasmodial and antimicrobial agents

This study presents an efficient one pot two steps synthesis of a new series of naturally occurring phenolic monoterpenoid based (thymol) benzimidazole derivatives (3a-i) by green approach. The structures of all newly synthesized benzimidazoles are confirmed by 1H NMR, 13C NMR, Mass, and FT-IR spectroscopic analyses. The synthesized compounds were examined for their in vitro antimalarial, antioxidant and antimicrobial activities. Antimalarial activity tested against P. falciparum strain, the IC50 values of all the tested compounds are in the range from 0.32 to 1.54 μg/mL. Biological screening revealed that some synthesized benzimidazoles possess very interesting biological activities. Molecular docking simulation against the potent inhibitors Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme indicated that potent compounds 3a, 3f, and 3 g have significant binding energy (-7.9 to −9.7 Kcal/mol). The in silico ADME properties estimated for the synthesized compounds indicated them as very good oral bioavailability drugs.

Discovery of dual-target natural antimalarial agents against DHODH and PMT of Plasmodium falciparum: pharmacophore modelling, molecular docking, quantum mechanics, and molecular dynamics simulations

ABSTRACT Malaria is a lethal disease that claims thousands of lives worldwide annually. The objective of this study was to identify new natural compounds that can target two P. falciparum enzymes; P. falciparum Dihydroorotate dehydrogenase (PfDHODH) and P. falciparum phosphoethanolamine methyltransferase (PfPMT). To accomplish this, e-pharmacophore modelling and molecular docking were employed against PfDHODH. Following this, 1201 natural compounds with docking scores of ≤ −7 kcal/mol were docked into the active site of the second enzyme PMT. The top nine compounds were subjected to further investigation using MM-GBSA free binding energy calculations and ADME analysis. The results revealed favourable free binding energy values better than the references, as well as acceptable pharmacokinetic properties. Compounds ZINC000013377887, ZINC000015113777, and ZINC000085595753 were scrutinized to assess their interaction stability with the PfDHODH enzyme, and chemical stability reactivity using molecular dynamics (MD) simulation and density functional theory (DFT) calculations. These findings indicate that the three natural compounds are potential candidates for dual PfDHODH and PfPMT inhibitors for malaria treatment.

Medicinal chemistry approaches for the discovery of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors as antimalarial agents.

Malaria is a severe human disease and a global health problembecause of drug-resistant strains. Drugs reported to prevent the growth of Plasmodium parasites target various phases of the parasites' life cycle. Antimalarial drugs can inhibit key enzymes that are responsible for the cellular growth and development of parasites. Plasmodium falciparum dihydroorotate dehydrogenase is one such enzyme that is necessary for de novo pyrimidine biosynthesis. This review focuses on various medicinal chemistry approaches used for the discovery and identification of selective P. falciparum dihydroorotate dehydrogenase inhibitors as antimalarial agents. This comprehensive review discusses recent advances in the selective therapeutic activity of distinct chemical classes of compounds as P. falciparum dihydroorotate dehydrogenase inhibitors and antimalarial drugs.

Screening Carica Papaya Compounds as an Antimalarial Agent: In Silico Study

Malaria is a highly prevalent infectious disease caused by the Plasmodium parasite transmitted through Anopheles mosquitoes, which poses a significant public health challenge worldwide, including in Indonesia. Therefore, a study was conducted to identify potential drug compounds from the Carica papaya plant that could inhibit various antimalarial proteins or receptors, such as Plasmodium falciparum DXR reductase complex with fosmidomycin, Plasmepsin V Plasmodium vivax, P. falciparum dihydroorotate dehydrogenase, P. falciparum hexose transporter, P. falciparum protein kinase 5, and P. falciparum dihydrofolate reductase-thymidylate synthase. Theresearchers used the Pyrx application to dock the C. papaya compounds with the targeted antimalarial proteins to determine the binding affinity values. Additionally, they used the Yasara dynamics application to conduct molecular dynamics simulation to ensure the stability of the bonds formed between the ligands and proteins. The results showed that 14 compounds found in C. papaya, particularly flavonoids and terpenoids, had the potential to inhibit the six antimalarial proteins with the lowest binding affinity values. Furthermore, the molecular dynamics simulation on 6M20 and 1V0P proteins indicated that the compounds effectively inhibited Plasmodium proteins, as they had an RMSD value below 2.5 Angstrom. The study suggests that C. papaya could be a potential source of antimalarial compounds, which could be developed into new drugs to combat this disease.&nbsp

Fragment-Based Drug Design, 2D-QSAR and DFT Calculation: Scaffolds of 1, 2, 4, triazolo [1, 5-a] pyrimidin-7-amines as Potential Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

Background: Plasmodium falciparum dihydroorotate dehydrogenase (PfDODH) is one of the enzymes currently explored in the treatment of malaria. Although there is currently no clinically approved drug targeting PfDODH, many of the compounds in clinical trials have [1, 2, 4,] triazolo [1, 5-a] pyrimidin- 7-amine backbone structure. Objective: This study sought to design new compounds from the fragments of known experimental inhibitors of PfDODH. Methods: Nine experimental compounds retrieved from Drug Bank online were downloaded and broken into fragments using the Schrodinger power shell; the fragments were recombined to generate new ligand structures using the BREED algorithm. The new compounds were docked with PfDODH crystal structure, after which the compounds were filtered with extensive drug-likeness and toxicity parameters. A 2D-QSAR model was built using the multiple linear regression method and externally validated. The electronic properties of the compounds were calculated using the density functional theory method. Results: Structural investigation of the six designed compounds, which had superior binding energies than the standard inhibitors, showed that five of them had [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine moieties and interacted with essential residues at the PfDODH binding site. In addition to their drug-like and pharmacokinetic properties, they also showed minimal toxicities. The externally validated 2D-QSAR model with R2 and Q2 values of 0.6852 and 0.6691 confirmed the inhibitory prowess of these compounds against PfDODH. The DFT calculations showed regions of the molecules prone to electrophilic and nucleophilic attacks. Conclusion: The current study thus provides insight into the development of a new set of potent PfDODH inhibitors.

In vitro antiplasmodial, molecular docking and pharmacokinetics studies of specialized metabolites from Tetrapleura tetraptera (Fabaceae)

Tetrapleura tetraptera is a well-known plant widely used in Cameroon as spices in cooking and in preparations prescribed in folk medicine for the treatment of malaria. The main purpose of this study was to provide relevant chemical and pharmacological insights that can support the effectiveness of T. tetraptera against malaria by identifying the lead compounds that may be responsible for its therapeutic potential. The stem bark and root methanolic crude extracts of this plant displayed a good inhibition of P. falciparum 3D7 with rates of 83.6% and 76.3%, respectively. A total of sixteen distinct compounds (1‒16) have been isolated during the chemical investigations of the two active crude extracts. Their structures were established with the aid of their NMR data. Thriteen compounds (2‒9, 11‒13, 15 and 16) were screened for antiplasmodial activity using P. falciparum 3D7. Results showed that seven tested compounds displayed good activity (IC50 < 7 μM) and the most effective were compounds 5, 9, 7, 2 and 6 with IC50 values of (1.8 ± 0.4 μM), (1.9 ± 0.8 μM), (2.1 ± 0.5 μM), (2.3 ± 0.7 μM), (2.4 ± 0.6 μM), respectively. The in silico evaluation of the isolated compounds for their ability to inhibit the P. falciparum dihydroorotate dehydrogenase 5TBO and their ADMET studies revealed that up to fifteen isolated compounds displayed a greater affinity to the binding site of the 5TBO receptor compared to the reference drug chloroquine. More especially, compounds 1, 2, 4, 8 and 14 demonstrated a good drug-likeness. These findings support the use of T. tetraptera for the management of malaria and further qualify it as an important source of good candidates in new antiplasmodial drug development.

Chemical Constituents of the Bark of Zanthoxylum gilletii (Rutaceae) and Their In Vitro Antiplasmodial and Molecular Docking Studies

The phytochemical investigations of the methanol extract of Zanthoxylum gilletii bark led to the isolation of thirteen compounds identified as two alkaloids including one acridone 5-hydroxynoracronycine (1) and one benzo [c] phenanthridine decarine (2), three lignans trans- and cis-fagaramide (3 and 4) and sesamin (5), two coumarins scoparone (6) and scopoletin (7), three pentacyclic triterpenoids fridelin (8), lupeol (9) and erythrodiol-3-O-palmitate (10), one phenolic compound vanillic acid (11) as well as two common steroids stigmasterol (12), and its derivative stigmasterol-3-O-β-D-glucopyranoside (13). The structures of all the isolated compounds were elucidated by means of their spectroscopic and spectrometric data (1D, 2D-NMR, MS) as well as the comparison of these data with those reported in the literature. Except for compounds 9 and 11–13, all the other isolated compounds are reported for the first time from Z. gilletii but have been already obtained from other Zanthoxylum species and in the Rutaceae family. Compounds 1, 3–5, and 9 were tested in vitro for their antiplasmodial potencies against Plasmodium falciparum 3D7, and the results revealed that all the tested compounds displayed an inhibition between 51.89% and 54.69% while only the mixture of 3 + 4 gave an IC50 lower than 10 000 nM (IC50 = 1333 nM). Furthermore, all the compounds have been evaluated in silico for their ability to inhibit the Plasmodium falciparum dihydroorotate dehydrogenase 5TBO. Sesamin (5) showed the greatest affinity to the antiplasmodium receptor than artemether® and chloroquine®. Further recorded data from their ADMET study, as well as their chemotaxonomy, are also discussed herein. The present study provides further information to enrich the chemistry of Z. gilletii and its qualification as an important source for good candidates in new antiplasmodial drug development.

Integrated structure-guided computational design of novel substituted quinolizin-4-ones as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a known drug target for the development of antimalarial agents. Herein, we presented integrated structure-guided computational strategies for the design of novel quinolizin-4-ones as PfDHODH inhibitors. PROCHECK and ERRAT analysis were performed for the validation of co-crystal structures of PfDHODH enzyme bound to the inhibitors available on PDB. Based on the results, PDB ID: 6i55 was selected for further structure-guided in silico studies. Five featured-based pharmacophore model (AADRR) was generated, and validated using GH scoring (0.74) and ROC analysis (0.94). Validated structure-based model was further used as a 3D search query to screen the ZINC database. Retrieved database compounds ZINC00386658, ZINC08439293, and ZINC09089086 were found in agreement with query features based on their highest fitness scores. HTVS, SP and XP docking studies with these retrieved hits demonstrated important interactions (His185. Arg265) with PfDHODH. Mapping of features of the pharmacophore model on these retrieved hits along with the role played by scaffolds and functional groups in docking study helped in the selection of quinolizin-4-one as a main scaffold and different functional groups for the design of novel compounds as PfDHODH inhibitors. In silico ADMET prediction study suggested that designed quinolizin-4-ones are “drug-like” candidates and can be synthesised without too many difficulties. In docking study of newly designed compounds, 8d exhibited the highest docking score of − 12.78 kcal/mol and formed important polar interactions (His185. Arg265) with the PfDHODH. PfDHODH-8d complex showed stable RMSD between 2.5 Å and 3 Å during 100 ns MD simulation study. The RMSD, RMSF and RoG analysis of the PfDHODH-8d complex indicated the absolute stability of the complex. Overall, combined in silico study identified quinolizin-4-ones as selective PfDHODH inhibitors.

Regioselective Synthesis of 5- and 3-Hydroxy-N-Aryl-1H-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).

Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies

Malaria, that ancient infectious disease is considered a great health problem due to its highly infectious and mortality rates. The more harmful kind of malaria is Plasmodium falciparum (Pf), accounting for over 1M fatalities yearly; unfortunately, existing medication regimens are hampered by resistance, necessitating the identification of novel targets against plasmodium species. Since the malaria parasite cannot recover pyrimidines, it must rely on de novo production to survive. Dihydroorotate dehydrogenase (DHODH), which facilitates the rate-limiting phase of that process, is therefore an interesting antimalarial target. In this context, computational screening comprising pharmacophore mapping, molecular docking, MM-GBSA calculations, ADME filtering and molecular dynamics were performed in order to identify novel and powerful PfDHODH inhibitors. A pharmacophore hypothesis with seven features was created and tested on 2 million compounds from the enamine database. Docking, MM-GBSA calculations, and ADME revealed ten hits with strong binding affinities and potential, stable binding energy, and drug-like properties. The top three hits were confirmed further using molecular dynamics simulations, which revealed that three of them were stable for the whole 100 ns simulation time. Relying on these findings, we recommend that Z1481646084, Z24317941, and Z951873618 be submitted for experimental verification as promising antimalarial gents.

Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target

BackgroundThe processes of drug development and validation are too expensive to be subjected to experimental trial and errors. Hence, the use of the insilico approach becomes imperative. To this effect, the drug-likeness and pharmacokinetic properties of the ten (10) previously designed derivatives of 2-anilino 4-amino substituted quinazolines were carried out. Their predicted ligand binding interactions were also carried out by docking them against the Plasmodium falciparum dihydroorotate dehydrogenase (Pf-DHODH) protein target, and the stability of the complex was determined through dynamic simulations. The drug-likeness and pharmacokinetic characteristics were estimated using the online SwissADME software, while the Molegro Virtual Docker (MVD) software was used for molecular docking. And the dynamic simulation was performed for the duration of 100 ns to verify the stability of the docked complex, with the aid of a Schrödinger program, Desmond.ResultsThe designed derivatives were all found to pass the Lipinski test of drug likeness, while the pharmacokinetic studies result that the skin permeability and molar refractivity values of the derivatives are both within the limits. In addition, except for derivative C-01, most of the derivatives have strong gastrointestinal absorptions and lack Pgp substrate. Furthermore, no derivative inhibited CYP1A2, CYP2C9, or CYP2C19. The docking studies show the better binding affinities between the ligands and Pf-DHODH than those between the atovaquone or chloroquine standards. The derivative C-02, {5-((6,7-dimethoxy-4-((3-nitrobenzyl)amino)quinazolin-2-yl)amino)-2-fluorobenzaldehyde} was found to be the most stable derivative, with a re-rank docking score of − 173.528 kcal/mol and interaction energy of − 225.112 kcal/mol. The dynamic simulation analysis shows that the derivative C-02 forms a stable complex with the protein target over the simulation time.ConclusionsThe ability of these ligands to form hydrogen bonds, as well as various other interactions, was cited as a factor responsible for their better binding affinity. These findings could aid further the development of enhanced antimalarial drugs.

Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.