ABSTRACT
OBJECTIVES: The Human Telomerase enzyme has become a drug target in the treatment of cancers and age-related disorders. This study aims to identify potential natural inhibitors of the Human Telomerase from compounds derived from edible African plants. MATERIALS AND METHODS: A library of 1,126 natural compounds was molecularly docked against the Telomerase Reverse Transcriptase (PDB ID: 5ugw), the catalytic subunit of the target protein. Curcumin, a known Telomerase inhibitor was used as the standard. The front-runner compounds were screened for bioavailability, pharmacokinetic properties, and bioactivity using the SWISSADME, PKCSM, and Molinspiration webservers respectively. The molecular dynamic simulation and analyses of the apo and holo proteins were performed by the Galaxy supercomputing webserver. RESULTS: The results of the molecular docking and virtual screening reveal Augustamine and Camptothecin as lead compounds. Augustamine has better drug-likeness and pharmacokinetic properties while Camptothecin showed better bioactivity and stronger binding affinity (-8.2 kcal/mol) with the target. The holo structure formed by Camptothecin showed greater inhibitory activity against the target with a total RMSF of 169.853, B-Factor of 20.164, and 108 anti-correlating residues. CONCLUSION: Though they both act at the same binding site, Camptothecin induces greater Telomerase inhibition and better molecular stability than the standard, Curcumin. Further tests are required to investigate the inhibitory activities of the lead compounds.
ABSTRACT
OBJECTIVE: To investigate the effect of phorbol 12-myristate 13-acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (FMLP) on oxygen consumption of differentiated and non-differentiated immune cell lines by retinoic acid and calcitriol treatment which might be useful in subsequent elicitation of immunological action during immunosuppressive states. METHODS: PMA and FMLP were used to artificially stimulate reactive oxygen production in cultured promonocytic U937 cell line. Paralleled samples of the cultured cells were separately prepared with calcitriol (1, 25- dihydroxyvitamin D3) and retinoic acid followed by a 72-hour incubation period. The rate of respiratory burst was measured using the Clark oxygen electrode. RESULTS: The average increase in cell concentrations per mL observed was significantly higher in retinoic acid-treated cells (9×10(6) cells/mL) when compared with calcitriol-treated samples (4×10(6) cells/mL). There was a marked increase in oxygen consumption of the calcitriol-treated cell lines against the retinoic acid-treated ones. Exposure of differentiated U937 cells to PMA and FMLP increased significantly (P<0.05) in their oxygen consumption when compared with the control. PMA calcitriol-treated cells resulted in 55% oxygen consumption more than the control while FMLP oxygen consumption increased 78% by comparison with the control. CONCLUSIONS: The result demonstrated that calcitriol may serve as a physiological promoter of normal differentiation of precursor cells which may exert an immunological action. This effect could elicit a marker potential and increase immune cell activity of the host especially in immunosuppressed diseased states.
