Computational drug discovery of potential 5α-reductase phytochemical inhibitors and hair growth promotion using in silico techniques

Abstract

Introduction: Male pattern hair loss (MPHL), also known as androgenetic alopecia (AGA), is a common disorder primarily caused by dihydrotestosterone (DHT). The Food and Drug Administration (FDA) has approved two 5-alpha reductase (5-AR) inhibitors-finasteride and dutasteride-for treating this condition. However, recent studies have reported adverse sexual side effects and issues with sperm production in young men using these medications. There are also recommendations for effectively treating hair loss with natural remedies, such as Urtica dioica (nettle), Serenoa repens (saw palmetto), and Trigonella foenum-graecum (fenugreek) that is mainly used for diminish the hair loss in the traditional medicine. Research shows that these herbal formulations and plant extracts may help reduce hair loss. However, the concentration of active compounds in these herbal extracts is often low, necessitating a large extract volume to achieve noticeable effects on hair growth. Although many studies have investigated the effects of these herbal extracts on hair growth, fewer studies focus on the specific compounds influencing the molecular mechanisms of hair loss, particularly the inhibition of 5-AR.

Methods: For the first time, we aimed to applied a computational study to explore the phytochemicals extracted from these herbs to identify compounds that can effectively bind to and inhibit 5-AR. Additionally, we assessed the stability of the ligands encapsulated in lipid nanoparticles (LNP) by conducting molecular dynamics (MD) simulations of the LNP-encapsulated ligands. We utilized an online database to identify compounds from the extracts of nettle, saw palmetto, and fenugreek. We then analyzed their binding affinity to 5-AR using computational techniques.

Results: We found that 6 molecules-Jamogenin, Neodiosgenin, Chlorogenic acid, Rutin, Riboflavin, and Ursolic acid-are effective in binding to 5-AR. Additionally, our in silico studies revealed that vesicle-entrapped JAMOGENIN, which has a stronger bond with 5-AR, is more stable than its unencapsulated form.

Discussion: Therefore, these 6 molecules, particularly JAMOGENIN, should be considered for experimental analysis in both their unencapsulated and nanocarrier-encapsulated states to promote hair follicle growth.

Keywords: 5α-reductase inhibitors; androgenetic alopecia; computational study; hair follicle growth; herbal extracts.

FIGURE 1

Schematic interaction of fenugreekine with 5-AR. The docked fenugreekine shows five conventional hydrogen bonds, two carbon and hydrogen bonds, three pi-cation bonds, and three pi-alkyl bonds with the binding pocket residues of 5-AR.

FIGURE 2

Secondary structures of the identified compounds: (A) riboflavin; (B) chlorogenic acid; (C) ursolic acid; (D) neodiosgenin; (E) jamogenin; (F) oleanolic acid.

FIGURE 3

Stability assessments of the ligands with 5-AR showing the (a) root mean-squared deviation (RMSD), (b) root mean-squared fluctuation (RMSF), and (c) radius of gyration (Rg) of the complex structures during 50 ns of molecular dynamics (MD) simulations. In all graphs, the complexes of 5-AR with chlorogenic acid, oleanolic acid, ursolic acid, jamogenin, neodiosgenin, and riboflavin are shown in gray, red, blue, green, purple, and mustard colors, respectively.

FIGURE 4

Schematic illustration of the structure of encapsulated jamogenin. The jamogenin molecule is located at the center of the bilayer vesicle, and the systemic environment contains ion molecules. The jamogenin and vesicle bilayer components are shown in red cartoon and milk-colored stick styles, respectively.

FIGURE 5

Stability assessments of the vesicle-enveloped and free (naked) jamogenin based on (a) RMSD and (b) Rg values during 20 ns of MD simulations. The vesicle-enveloped and free jamogenin are shown in blue and red colors, respectively.