Antileishmanial natural products as potential inhibitors of the Leishmania pteridine reductase: insights from molecular docking and molecular dynamics simulations.

Although many natural product-derived compounds possess anti-leishmanial activities in vitro and in vivo, their molecular targets in the Leishmania parasite remain elusive. This is a major challenge in optimizing these compounds into leads. The Leishmania pteridine reductase (PTR1) is peculiar for folate and pterin metabolism and has been validated as a drug target. In this study, 17 compounds with anti-leishmanial activities were screened against Leishmania major PTR1 (LmPTR1) using molecular docking and molecular dynamics (MD) simulations. All ligands were bound in the active site pocket of LmPTR1 with binding affinities ranging from -11.2 to -5.2 kcal/mol. Agnuside, betulin, betulinic acid, gerberinol, ismailin, oleanolic acid, pristimerin, and ursolic acid demonstrated binding affinities similar to a known inhibitor, methyl 1-(4-{[2,4-diaminopteridin-6-yl) methyl] amino} benzoyl) piperidine-4-carboxylate (DVP). MD simulations revealed that betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid formed stable complexes with LmPTR1. The binding free energies of the complexes were very good (-87 to -148 kJ/mol), and much higher than the complex of the standard DVP inhibitor and LmPTR1 (-27 kJ/mol). Betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid likely exert their antileishmanial action by inhibiting PTR1 and could thus be used as a basis for the development of potential antileishmanial chemotherapeutic agents. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00247-8.

Oplodiol and nitidine as potential inhibitors of Plasmodium falciparum dihydrofolate reductase: insights from a computational study.

Many natural products have been shown to possess antiplasmodial activities, but their protein targets are unknown. This work employed molecular docking and molecular dynamics simulations to explore the inhibitory activity of some antiplasmodial natural products against wild-type and mutant strains of Plasmodium falciparum dihydrofolate reductase (PfDHFR). From the molecular docking study, 6 ligands preferentially bind at the active site of the DHFR domain with binding energies ranging from -6.4 to -9.5 kcal/mol. Interactions of compounds with MET55 and PHE58 were mostly observed in the molecular docking study. From the molecular dynamics study, the binding of 2 of the ligands-nitidine and oplodiol-was observed to be stable against all tested strains of PfDHFR. The average binding free energy of oplodiol in complex with the various PfDHFR strains was -93.701 kJ/mol whereas that of nitidine was -106.206 kJ/mol. The impressive in silico activities of the 2 compounds suggest they could be considered for development as potential antifolate agents.Communicated by Ramaswamy H. Sarma.

Molecular insights into the differential membrane targeting of maximin 1 in prokaryotic and eukaryotic cells.

Antimicrobial resistance is a pressing global health concern, underscoring the need for alternative treatments. Antimicrobial peptides (AMPs) have shown promise in this regard, with maximin 1 being a cationic, amphipathic AMP possessing antibacterial, antifungal, and antiviral activities with low hemolytic activity. In this study, we used molecular dynamics simulation to investigate the molecular basis for membrane selectivity of Maximin 1. By studying interactions between maximin 1 and different models of prokaryotic (anionic) and eukaryotic (zwitterionic) membranes, we found that Maximin 1 interacts more strongly with the prokaryotic membrane due to electrostatic attraction, while it weakly interacts with the zwitterionic eukaryotic membrane. Our simulations also revealed that Gly-1, Lys-5, Lys-11, Lys-15, and Lys-19 were identified to play a crucial role in the adsorption of maximin unto the prokaryotic membrane surface. The alpha-helical nature of the peptide, in addition to its amphipathic nature, was necessary for the adsorption of the peptide onto the surface of the prokaryotic membrane. Interestingly, the later transition of the alpha helix into a random coil was crucial in penetrating the prokaryotic membrane while hindering interactions with the eukaryotic membrane. Residues in the middle region of the peptide (residues 9-16) were also responsible for permeating the prokaryotic membrane over the eukaryotic membrane. These findings shed light on the peptide's selective targeting of bacterial membranes over human cell membranes and could inform the design of more effective AMPs.Communicated by Ramaswamy H. Sarma.

The Amaryllidaceae alkaloid, montanine, is a potential inhibitor of the Trypanosoma cruzi trans-sialidase enzyme.

Trypanosoma cruzi is the parasite that causes the chronic malady known as Chagas disease (CD). Only nifurtimox and benznidazole are currently approved to treat CD in acute and chronic phases. To minimize the danger of disease transmission and as a therapy, new compounds that are safer and more effective are required. It has been demonstrated that Amaryllidaceae plants suppress the growth of T. cruzi - the causative agent of CD. However, little research has been done on their potential protein targets in the parasite. In this study, an in-silico approach was used to investigate the interactions of the Amaryllidaceae alkaloids with trans-sialidase, a confirmed protein target of T. cruzi. The nature and efficiency of the main binding modes of the alkaloids were investigated by molecular docking. Trans-sialidase active site residues were bound by the alkaloids with binding energies varying from -8.9 to -6.9 kcal/mol. From the molecular docking investigation, all the alkaloids had strong interactions with the crucial amino acid residues (Glu230, Tyr342, and Asp59) required for trans-sialidase catalysis. Montanine was the most stable compound throughout the molecular dynamics simulation and had a favorable docking binding energy (-8.9 kcal/mol). The binding free energy (MM-GBSA) of the montanine complex was -14.6 kcal/mol. The pharmacokinetic properties investigated demonstrated that all the evaluated compounds exhibit suitable oral administration requirements. Overall, this in silico study suggests that the Amaryllidaceae alkaloids could potentially act as inhibitors of trans-sialidase.Communicated by Ramaswamy H. Sarma.

In silico identification of α-bisabolol and letestuianin C as potential inhibitors of Trypanosoma brucei trypanothione reductase.

Despite the recent advances in drug research, finding a safe, effective, and easy to use chemotherapy for human African trypanosomiasis (HAT) remains a challenging task. Trypanosomatids have developed resistance mechanisms towards melarsoprol (the current drug of choice), and the fact that it is poisonous is problematic. Therefore, a search for alternative therapeutics against the parasite is urgently needed. Natural products offer potential for drug discovery, but little or nothing is known about the target of inhibition or possible mode of inhibition. Therefore, this study aimed to use molecular docking and molecular dynamics simulations to evaluate 30 antitrypanosomal natural products as potential inhibitors of trypanothione reductase, a key protein necessary for the survival of the Trypanosoma brucei. The study also assessed the pharmacokinetic properties of the most promising compounds. Of the compounds evaluated, α-bisabolol, letestuianin C, waltherione, and mexicanin E were found to bind at the active site of TR and interact with Met115, Tyr112, and Trp23, which are essential for enzyme functioning. Molecular dynamic simulations revealed the sustained binding of α-bisabolol and letestuianin C throughout the simulation period, potentially obstructing the binding of the substrate (T[S]2) and impeding catalysis. The binding of these compounds to TR led to the presence of solvent molecules in the enzyme's active site, and this could potentially lead to protein aggregation. Furthermore, α-bisabolol and letestuianin C exhibited promising safety profiles. Consequently, α-bisabolol and letestuianin C have been shown to be viable candidates for targeting trypanothione reductase in the fight against human African trypanosomiasis.Communicated by Ramaswamy H. Sarma.

Computational studies on potential small molecule inhibitors of Leishmania pteridine reductase 1.

Leishmaniasis is a neglected tropical disease of major public health concern. Challenges with current therapeutics have led to the exploration of plant medicine for potential antileishmanial agents. Despite the promising activity of some antileishmanial natural products, their protein targets have not been explored. The relevance of folate metabolism in the Leishmania parasite's existence presents crucial targets for the development of antileishmanial chemotherapy. Pteridine reductase 1 (PTR1), a crucial enzyme involved in DNA biosynthesis, is a validated target of the Leishmania parasite. Unearthing inhibitors of this enzyme is therefore an active research area. The goal of this work is to unearth small molecule inhibitors of PTR1 using molecular docking and molecular dynamic simulations. Thus, the interactions between selected antileishmanial natural products and PTR1 were examined. The binding affinities obtained from molecular docking ranged from -6.2 to -9.8 kcal/mol. When compared to the natural PTR1 substrate biopterin, compounds such as anonaine, chimanine D, corynantheine, grifolin, licochalcone A, piperogalin and xylopine produced better binding affinities, making interactions catalytic residues - Tyr194, Asp181, Phe113, Arg17 and Ser111. The PTR1- xylopine, -piperogalin, -grifolin, and -licochalcone A complexes exhibited remarkable stability under dynamic conditions during the entire 200 ns simulation period. The overall binding free energy of grifolin, piperogalin, and licochalcone A were observed to be -105.711, -103.567, and -105.646 kJ/mol respectively. The binding of these complexes was observed to be favorable and spontaneous and as such capable of inhibiting Leishmania PTR1. They could therefore be considered as candidates in the development of antileishmanial chemotherapy.Communicated by Ramaswamy H. Sarma.

Essential Oils from the Fruits and Leaves of Spondias mombin Linn.: Chemical Composition, Biological Activity, and Molecular Docking Study.

This work focused on characterizing the chemical constituents and evaluating the antioxidant and antimicrobial activities of the essential oils obtained from the fruit and leaves of Spondias mombin-a flowering plant of the Anacardiaceae family. Essential oils were extracted through steam distillation and characterized by gas chromatography-mass spectrometry. For the fruit essential oil, 35 compounds were obtained, and 25 compounds were identified in the leaf essential oil. The dominant compounds present in the fruit essential oil were (E)-ethyl cinnamate (14.06%) and benzyl benzoate (12.27%). Methyl salicylate (13.05%) and heptacosane (12.69%) were the abundant compounds in the leaf essential oil. The antioxidant activity of the essential oils was evaluated via phosphomolybdenum, hydrogen peroxide scavenging, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, and thiobarbituric acid reactive substances (TBARS) assays. The total antioxidant capacity of fruit and leaf essential oils was 48.5 ± 0.7 µg/gAAE and 48.5 ± 0.7 µg/g AAE, respectively. The half maximal scavenging concentrations of the essential oils in the hydrogen peroxide; DPPH and TBARS assays ranged from 252.2 µg/mL to 2288 µg/mL. The antimicrobial activity of the essential oils was tested using broth dilution and disc diffusion assays against eight microorganisms. The essential oils exhibited broad-spectrum antimicrobial activity against the microorganisms with minimum inhibitory concentrations of 9.75-50 mg/mL. Also, the zones of inhibition of the oils ranged from 12 mm to 25 mm. The biofilm inhibitory activities of the oils were dose-dependent with BIC50 values of 42.49 ± 0.1 mg/mL and 97.34 ± 0.6 mg/mL for fruit and leaf essential oils, respectively. Molecular docking studies revealed that the antibiofilm action of the fruit and leaf essential oils could be due to inhibition of the quorum sensing protein, LasR. The results suggest a possible application of the oils as antioxidant and antimicrobial agents.

N-alkylimidazole derivatives as potential inhibitors of quorum sensing in Pseudomonas aeruginosa.

Antimicrobial resistance is a threat to global public health. Microbial resistance is mediated by biofilm formation and virulence behavior during infection. Quorum sensing (QS), a cell-to-cell communication is frequently used by microbes to evade host immune systems. Inhibiting QS channels is a potential route to halt microbial activities and eliminate them. Imidazole has been shown to be a potent warhead in various antimicrobial agents. This study aims to evaluate alkyl-imidazole derivatives as potential inhibitors of QS and to explore the interactions of the compounds with LasR, a key protein in the QS machinery of Pseudomonas aeruginosa. The study revealed that imidazole derivatives with longer alkyl chains possessed better antimicrobial activities. Octylimidazole and decylimidazole emerged as compounds with better anti-virulence and biofilm inhibition properties while hexylimidazole showed the best inhibitory activity against Pseudomonas aeruginosa PAO1. The binding affinity of the compounds with LasR followed a similar trend as that observed in the QS inhibitory assays, suggesting that interaction with LasR may be important for QS inhibition.

Alkaloids from Cryptolepis sanguinolenta as Potential Inhibitors of SARS-CoV-2 Viral Proteins: An In Silico Study.

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.