Title:Docking and Simulation Studies on Novel Analogues of 3,4,5-Trihydroxy Benzoic Acid as HSP90Alpha Inhibitors
Volume: 22
Issue: 3
Author(s): Tanya Gupta, Ritu Kataria, Asim Kumar, Rubina Bhutani and Satish Sardana*
Affiliation:
- Amity Institute of Pharmacy, Amity University, Haryana, Gurugram, 122413, India
Keywords:
Ciprofloxacin, simulation, gallic acid, dynamics, conformation, bioactivity, modulators and HSP90alpha.
Abstract: HSP90 assists as a crucial molecular chaperone that responds to environmental stressors
and helps in the survival of cells in microorganisms. This protein is integral to the stress response,
aiding in the stabilization of various proteins essential for microbial survival. Consequently, the ability
of a number of tissues to adjust to endogenous stress depends critically on appropriate chaperone
activity. Modulators of chaperone activity, however, have emerged as a novel and developing area of
drug discovery due to the association between changed chaperone function and the development of
numerous illnesses. Inhibition of HSP90alpha can disrupt proper protein folding, thus impairing
growth and virulence in fungi. In this work, we selected novel leads of gallic acid derivatives with the
help of OSIRIS Property Explorer and DruLiTo software. Selected leads were subjected to ADME-T
studies for further screening. Docking and molecular simulation studies on selected compounds were
performed using Schrodinger v21 and GROMACS software to predict the bioactivity of novel leads
of 3,4,5 trihydroxy benzoic acid for suppression of the HSP90alpha enzyme. Compounds 4N, 18N,
15N, and 14N showed good docking scores of -6.5, -6.4, -5.91, and -5.98, respectively, which was
comparable to standard ciprofloxacin. Compound 4N and compound 14N demonstrated notable binding
interactions and were selected for further investigation through molecular dynamics studies with
HSP90alpha (PDB ID: 1YC1). RMSD, H BOND, and RMSF analysis confirmed the stable binding of
compounds 4N and 14 N with the HSP90 enzyme. The RMSF plot showed less than 0.35 nm fluctuation
for the HSP90alpha enzyme in complex with different ligands. It can be concluded that ligand
binding can cause stability to the conformation of the protein. Compounds 4N and 14N are considered
to be the best theoretical lead, which can further be studied experimentally as HSP90 alpha inhibitors
for antimicrobial activity.
