Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies.

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (-11.569 to -7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of -10.643 and -10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of -67.96 and -50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery.

Discovery of novel natural products as rhodesain inhibitors for human African trypanosomiasis using in silico techniques.

Human African Trypanosomiasis (HAT) or sleeping sickness is caused by the Trypanosoma brucei rhodesiense, a subspecies of the Trypanosomatide family. The parasite is associated with high morbidity and mortality rate in both animals and humans, claimed to be more fatal than other vector-transmitted diseases such as malaria. The majority of existing medications are highly toxic, not effective in the late chronic phase of the disease, and require maximum dosages to fully eradicate the parasite. In this study, we used computational methods to find out natural products that inhibit the Rhodesain, a parasitic enzyme that plays an important role in the parasite's pathogenicity, multiplication, and ability to pass through the host's blood-brain barrier. A library of 270540 natural products from ZINC databases was processed by using e-pharmacophore hypnosis and screening procedures, molecular docking, ADMET processes, and MM-GBSA calculations. This led to the identification of 3 compounds (ZINC000096269390, ZINC000035485292, and ZINC000035485242) which were then subjected to molecular dynamics. The findings of this study showed excellent binding affinity and stability toward the Rhodesain and suggest they may be a hopeful treatment for HAT in the future if further clinical trials were performed.Communicated by Ramaswamy H. Sarma.

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies.

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2.