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

Summary

Here, we present a protocol for the structure-guided design of protein-ligand binding interaction between Sanglifehrin A and Cyclophilin A/Ganoderiol-F, essential in discovering new drugs. The stability of the ligand-receptor complex was evaluated using molecular dynamics simulation.

Abstract

The cyclin Ds-CDKs axis (Cyclophilin A (Cyp /Ganoderiol F)) plays a critical role in cancer through various processes, such as controlling proliferation and inhibiting cancer cells. Ganoderiol F derivatives can serve as oncogenic targets for multiple cancer types. This study demonstrated that the structure-guided design and development of novel Cyp A inhibitors and Ganoderiol F derivatives can be employed to select calculated positions for increased effectiveness in chemical inhibitors and their interaction with the chosen receptors. For this approach, numerous software applications were utilized to achieve optimal molecular interactions. Overall, 117 novel cyclophilin inhibitor ligand molecules were constructed using Chemsketch software. The converted PDB files of the novel Cyp A inhibitor ligands were prepared for introduction to the Sanglifehrin A enzyme receptor. Ligand-protein docking interactions were performed using AutoDock 4.2.6 software to reveal the best geometric interactions. The docking confirmations were carried out using PyMOL 2.5 software. Finally, hydrogen bonds were detected using Chimera and Maestro software. The selected ligand-receptor docked complex was subjected to molecular dynamics simulation. The MD simulation process demonstrated the stability of the complex and indicated that the chosen ligand can be utilized as a drug inhibitor for cancer cells. In the results, the active amino acids in binding site were identified as Arginine 55 that in motion of 1.53Å, Asparagine (Asn), Glycine (Gly), Threonine (Thr), Lysine (Lys), Isoleucine (Iso), Histidine (Hid), Phenylalanine (Phe), and Cysteine (Cys) with the highest number of hydrogen bond ligand of 45 hydroxymangiferonic. That connected with 1nmk receptor in grid box coordinate of X 38.86, Y of 10.987, and Z of 40.734. The 1nmk receptor-ligand complex evaluation in molecular dynamics (MD) simulation in Gromacs version CHARMM 36 force field has optimum degrees.

Introduction

Cyclophilin A is a strong inhibitor of human Cyp A. Cyclophilin is a robust inhibitor that does not impair the immune system, possesses better pharmacological qualities, and reduces transporter inhibition. Poor prognosis has been linked to the overexpression of cyclophilins, a family of proteins with peptidyl-prolyl isomerase activity¹. Cyclophilins have been reported to be overexpressed in numerous cancers, including hepatocellular carcinoma. In hepatocellular carcinoma (HCC), cyclophilins are crucial for both cancer drug resistance and proliferation². The inhibition acquires essential information to identify new immuno....

Protocol

1. In silico generation of ligands and ligand preparations in ChemSketch software

NOTE: This software will be used to draw the structure of a ligand/molecule, i.e., molecular editing.

1. Draw the ligand/structure as indicated in the drawing process followed in the software, as shown in Supplementary File 1 (Screenshot 1).
2. Press f9 to clean the structure after drawing the complete structure.
3. Click on File and then Save As. (Navigate to the folder, e.g., molecule 1 will be saved in folder 1, and so on).
4. Change the Save A....

Results

As mentioned in the introduction, in vivo and in vitro studies demonstrate the importance of cyclophilin inhibitors in simplifying the structure of Sanglifehrin, thereby reducing mouse spleen proliferation by interfering with the mouse cell cycle⁵. In addition, Cyclophilin A, along with Ganoderiol F derivatives, plays vital roles in protein folding, immune responses, and cell signaling through its PPIASE activity. Its upregulation in various cancers suggests its potential as a th.......

Discussion

A new immunosuppressive natural substance called SFA or 1nmk molecular receptor was extracted from Streptomyces. Molecular docking analysis was used to determine the binding energies of the constructed ligands with the target protein. The results showed that, of all the designed ligands, SFA differs structurally from CsA and exhibits a considerable affinity for Cyp A¹⁶. Cyp A, which possesses peptidyl-prolyl cis-trans isomerase activity, controls a variety of cellular processes by attachi.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Autodock	Autodock	v4.2.6	http://autodock.scripps.edu/downloads/autodock-registration/autodock-4-2-download-page/
CGenFF	CGenFF	v2024	https://cgenff.umaryland.edu
Chemsketch	Chemsketch	v2024	http://www.acdlabs.com/resources/freeware/
Cygwin terminal	Cygwin terminal	v3.6.3	http://www.cygwin.com/
Gromacs tutorial	Gromacs tutorial	v25.04 (Plucky Puffin)	http://www.mdtutorials.com/gmx/complex/index.html
MGL tools	MGL tools	v1.5.7	mgl tools 1.5.6 rc3
Open babel	Open babel	v3.1.1	http://openbabel.org/wiki/main_page
PyMOL	PyMOL	v3.1.6.1	PyMOL | pymol.org
Ubuntu	Ubuntu	v25.04l	https://ubuntu.com/download/desktop
UCSF chimera	UCSF chimera	v1.19	chimera-1.17.3-win64.exe