Binding mechanism of andrographolide with intramolecular antiparallel G-quadruplexes of therapeutic importance: an in-silico analysis

Abstract

ABSTRACT G-quadruplexes are non-canonical DNA structures that emerged as important drug targets. Andrographolide is a plant-derived compound with various pharmacological properties. The binding of andrographolide with CREB1 G-quadruplex and Thrombin Binding Aptamer (TBA) was estimated using molecular docking, dynamics, and simulation. The data demonstrated the stabilising effect of the ligand on G-quadruplexes. Andrographolide binds to the CREB1 G-quadruplex by forming hydrogen bonds with the terminal residues and thymine and cytosine residues in the loop region with a binding energy of – 7.30 kcal/mol. At the same time, the TBA G-quadruplex structure formed hydrogen bonds with the residues in the quartet and loop region with binding energy – 6.61 kcal/mol. The Molecular Mechanics Poisson-Boltzmann Surface Area analysis revealed that the contribution from electrostatic energy is higher (−109.21 ± 51.40 KJ/mol) for CREB1 than for TBA (−41.49 ± 27.25 KJ/mol). Principle component analysis illustrated that the eigenvalues are much higher for the unbound forms than for the ligand-bound forms. These findings indicate that andrographolide could potentially target G-quadruplex forming DNA sequences in various oncogenes and can have multiple therapeutic applications.