Anthelmintic screening of Bangladeshi medicinal plants and related phytochemicals using in vitro and in silico methods: An ethnobotanical perspective.

ETHNOPHARMACOLOGICAL RELEVANCE: Infections caused by parasitic worms or helminth continue to pose a great burden on human and animal health, particularly in underdeveloped tropical and subtropical countries where they are endemic. Current anthelmintic drugs present serious limitations and the emergence of drug resistance has made it increasingly challenging to combat such infections (helminthiases). In Bangladesh, medicinal plants are often used by indigenous communities for the treatment of helminthiases. Knowledge on such plants along with screening for their anthelmintic activity has the potential to lead to the discovery of phytochemicals that could serve as novel molecular scaffolds for the development of new anthelminthic drugs. AIM OF THE STUDY: The purpose of this study was i) to conduct an ethnobotanical survey to gather data on Bangladeshi medicinal plants used in the treatment of helminthiases, ii) to test plants with the highest use values for their in vitro anthelmintic activity, and iii) to carry out in silico screening on phytochemicals present in the most active plant extract to investigate their ability to disrupt ß-tubulin function in helminths. METHODS: The ethnobotanical survey was conducted across three sub-districts of Bangladesh, namely Mathbaria, Phultala and Khan Jahan Ali. The in vitro screening for anthelmintic activity was performed in a motility test using adult Haemonchus contortus worms. Virtual screening using PyRx was performed on the phytochemicals reported from the most active plant, exploring their interactions with the colchicine binding site of the ß-tubulin protein target (PDB ID: 1SA0). RESULTS: The survey respondents reported a total of 32 plants for treating helminthiases. Based on their use values, the most popular choices were Ananas comosus (L.) Merr., Azadirachta indica A.Juss., Carica papaya L., Citrus maxima (Burm.) Merr., Curcuma longa L., Momordica charantia L., Nigella sativa L. and Syzygium cumini (L.) Skeels. In vitro anthelmintic testing revealed that A. indica leaves and bark had the highest activity with LC50 values of 16 mg/mL in both cases. Other plant extracts also exhibited good anthelmintic activity with LC50 values ranging from 16 to 52 mg/mL, while the value for albendazole (positive control) was 8.39 mg/mL. The limonoids nimbolide and 28-deoxonimbolide showed a binding affinity of -8.9 kcal/mol, and satisfied all drug-likeness parameters. The control ligand N-deacetyl-N-(2-mercaptoacetyl)colchicine had a binding affinity of -6.9 kcal/mol. CONCLUSION: Further in silico and in vitro studies are warranted on the identified limonoids to confirm the potential of these derivatives as novel drug templates for helminthiases. The current study supports the need for an ethnobotanical survey-based approach to discover novel drug templates for helminthiases.

Investigation of the anti-TB potential of selected propolis constituents using a molecular docking approach.

Human tuberculosis (TB), caused by Mycobacterium tuberculosis, is the leading bacterial killer disease worldwide and new anti-TB drugs are urgently needed. Natural remedies have long played an important role in medicine and continue to provide some inspiring templates for drug design. Propolis, a substance naturally-produced by bees upon collection of plant resins, is used in folk medicine for its beneficial anti-TB activity. In this study, we used a molecular docking approach to investigate the interactions between selected propolis constituents and four 'druggable' proteins involved in vital physiological functions in M. tuberculosis, namely MtPanK, MtDprE1, MtPknB and MtKasA. The docking score for ligands towards each protein was calculated to estimate the binding free energy, with the best docking score (lowest energy value) indicating the highest predicted ligand/protein affinity. Specific interactions were also explored to understand the nature of intermolecular bonds between the most active ligands and the protein binding site residues. The lignan (+)-sesamin displayed the best docking score towards MtDprE1 (-10.7 kcal/mol) while the prenylated flavonoid isonymphaeol D docked strongly with MtKasA (-9.7 kcal/mol). Both compounds showed docking scores superior to the control inhibitors and represent potentially interesting scaffolds for further in vitro biological evaluation and anti-TB drug design.

Interaction of Quercetin of Onion with Axon Guidance Protein Receptor, NRP-1 Plays Important Role in Cancer Treatment: An In Silico Approach.

Neuropilin-1 (NRP-1) is a transmembrane glycoprotein receptor whose distinct sites bind semaphorins and vascular endothelial growth factor family members to mediate the role of these ligands in neuronal axon guidance and angiogenesis, respectively. Similarly, Eph receptors and ephrin ligands play critical roles in various biological functions, and deregulated activation of Eph/ephrin signaling in humans is thought to lead to tumorigenesis. Therefore, in this paper, an attempt was made to elucidate the inhibition potential of nine bioactive compounds from four different native spices of Bangladesh against this couple of receptors via molecular docking study. The molecular docking study was carried out using Vina docking protocol. Finally, the receptor-ligand interaction analysis was carried out using the Discovery Studio Client package. Quercetin and diosgenin of onion showed favorable binding with NRP-1 with low binding energy of -7.8 and -7.2 kcal/mol, respectively, in comparison with the control inhibitor (-6.1 kcal/mol). The study suggests that ligand interaction with the residues Asp 48, Thr 44, Thr 77, Tyr 81, Trp29, Ile 143 of NRP-1 and Lys 653, Phe 765, Ser 763, Thr 699, Ile 683 of Eph might be critical for the inhibitory activity of these receptors. The study provides evidence for consideration of quercetin and diosgenin of onion as valuable small ligand molecules for targeting NRP-1 receptor in treatment and prevention of neurological disorders as well as cancer.

Treating Diabetes Mellitus: Pharmacophore Based Designing of Potential Drugs from Gymnema sylvestre against Insulin Receptor Protein.

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders which can affect the quality of life severely. Injectable insulin is currently being used to treat DM which is mainly associated with patient inconvenience. Small molecules that can act as insulin receptor (IR) agonist would be better alternatives to insulin injection. Herein, ten bioactive small compounds derived from Gymnema sylvestre (G. sylvestre) were chosen to determine their IR binding affinity and ADMET properties using a combined approach of molecular docking study and computational pharmacokinetic elucidation. Designing structural analogues were also performed for the compounds associated with toxicity and less IR affinity. Among the ten parent compounds, six were found to have significant pharmacokinetic properties with considerable binding affinity towards IR while four compounds were associated with toxicity and less IR affinity. Among the forty structural analogues, four compounds demonstrated considerably increased binding affinity towards IR and less toxicity compared with parent compounds. Finally, molecular interaction analysis revealed that six parent compounds and four analogues interact with the active site amino acids of IR. So this study would be a way to identify new therapeutics and alternatives to insulin for diabetic patients.