Camptothecin shows better promise than Curcumin in the inhibition of the Human Telomerase: A computational study

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.

Keywords: Augustamine; Camptothecin; Molecular dynamic simulation; Pharmacokinetic; Telomerase.

Figure 1

Cartoon model of the crystal structure of Human Telomerase (PDB ID: 5ugw). b: Surface representation.

Figure 2

Ramachandran plot for Human Telomerase (PDB ID: 5ugw).

Figure 3

The 3D chemical structures (stick model) of standard and lead compounds a: Curcumin b: Augustamine c: Camptothecin.

Figure 4

Binding site of Human Telomerase interacting with standard and lead compounds a: hTERT-Curcumin complex b: hTERT-Augustamine c: hTERT-Camptothecin complex.

Figure 5

Protein-Ligand interactions of Human Telomerase with standard and lead compounds a: hTERT-Curcumin complex b: hTERT-Augustamine c: hTERT-Camptothecin complex.

Figure 6

Cartoon model of the crystal structure of Human Telomerase Apo and Holo structures (without water and ions) after molecular dynamics simulation. Beta sheets (yellow), Alpha helix (red) and Loops (green) a: hTERT b: hTERT-Curcumin complex c: hTERT-Augustamine complex d: hTERT-Camptothecin complex.

Figure 7

RMSD for Apo and Holo structures a: hTERT b: hTERT-Curcumin complex c: hTERT-Augustamine complex d: hTERT-Camptothecin complex.

Figure 8

RMSD histogram for Apo and Holo structures a: hTERT b: hTERT-Curcumin complex c: hTERT-Augustamine complex d: hTERT-Camptothecin complex.

Figure 9

Per-residue RMSF for Apo and Holo structures a: hTERT b: hTERT-Curcumin complex c: hTERT-Augustamine complex d: hTERT-Camptothecin complex.

Figure 10

Principal component analysis cluster plot of Apo and Holo structures. The projection of trajectory onto 1st few eigenvectors for: a: hTERT b: hTERT-Curcumin complex c: hTERT-Augustamine complex d: hTERT-Camptothecin complex.

Figure 11

Dynamic cross correlation map apo and holo structures of SARS-CoV-2 2′ OMT. Purple represents anti-correlated, dark cyan represents fully correlated while white and cyan represent moderately and uncorrelated respectively. 1.0 = correlated; 0 is non-correlated; and -1 is anti-correlated. a: hTERT b: hTERT-Curcumin complex c: hTERT-Augustamine complex d: hTERT-Camptothecin complex.

Figure 12

Hydrogen Bond Stability during MDS. hTERT Apo (Blue), hTERT-Curcumin complex (Red), hTERT-Augustamine complex (Grey), hTERT-Camptothecin complex (Yellow).