Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico...

Area of Science:

• Medicinal Chemistry
• Computational Biology
• Oncology

Background:

• The cyclin Ds-CDKs axis, involving Cyclophilin A (Cyp A) and Ganoderiol F, is crucial in cancer progression.
• Ganoderiol F derivatives show promise as oncogenic targets for various cancer types.

Purpose of the Study:

• To design and develop novel Cyp A inhibitors and Ganoderiol F derivatives for cancer therapy.
• To optimize inhibitor effectiveness and receptor interaction through structure-guided design.
• To computationally evaluate potential drug candidates for cancer treatment.

Main Methods:

• Structure-guided design and molecular modeling using Chemsketch, AutoDock 4.2.6, PyMOL, Chimera, and Maestro.
• Construction of 117 novel cyclophilin inhibitor ligand molecules.
• Ligand-protein docking, docking confirmation, hydrogen bond detection, and molecular dynamics (MD) simulations using Gromacs with CHARMM 36 force field.

Main Results:

• Identified active amino acids in the binding site, including Arginine 55, Asparagine, Glycine, Threonine, Lysine, Isoleucine, Histidine, Phenylalanine, and Cysteine.
• Determined the optimal grid box coordinates (X: 38.86, Y: 10.987, Z: 40.734) for the 1nmk receptor-ligand complex.
• MD simulations confirmed the stability of the selected ligand-receptor complex, indicating its potential as a cancer drug inhibitor.

Conclusions:

• Novel Cyp A inhibitors and Ganoderiol F derivatives can be effectively designed using computational methods.
• The identified ligand-receptor complex demonstrates stability and potential for development as an anti-cancer therapeutic agent.
• This study provides a foundation for further investigation into these compounds for cancer treatment.