A SARM a Day Keeps the Weakness Away: A Computational Approach for Selective Androgen Receptor Modulators (SARMs) and Their Interactions with Androgen Receptor and 5‑Alpha Reductase Proteins

Abstract

This study examines the molecular interactions of selective androgen receptor modulators (SARMs) with the androgen receptor (AR) and 5-alpha reductase II (5αRII), highlighting their potential as dual-action pharmacological candidates, using molecular modeling techniques to evaluate their primary interactions, providing valuable insights into conformational stability and ligand-induced changes and enabling rational analysis of SARMs with optimized pharmacological profiles. Employing molecular docking, density functional theory (DFT), and molecular dynamics simulations, we analyzed the binding affinities and conformational stability. Between all eight SARMs tested, 4'-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2'-(trifluoromethyl)-benzonitrile (Sarm2f) demonstrated exceptional stability and binding affinity with critical interactions at key AR residues such as Asn705, Glu711, Arg752, and Thr877. The inclusion of fluorinated groups enhances hydrogen bonding through dipole induction, improving the binding dynamics. Additionally, Sarm2f interacts with small hydrophobic pockets around the 5-oxopyrrolidine ring, further stabilizing its conformation. Also, (17α,20E)-17,20-[(1-methoxyethylidene)-bis-(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11) exhibited compelling interactions with both AR and 5αRII, characterized by a tetracyclic steroidal nucleus that enhances its androgenic activity. Structural modifications, including a double bond at the C20 position in YK11, improve stability and prolong interactions with the AR. While Sarm2f shows lower root-mean-square deviation (RMSD) values, indicating rigidity, the slight flexibility of YK11 may allow for a broader range of interactions. These findings emphasize the importance of advanced computational methods in optimizing SARMs by demonstrating how specific chemical modifications affect binding affinity and selectivity for AR and 5αRII, thereby aiding the development of safer and more effective pharmacological agents for androgen-related conditions.

1

SARMs structures selected for affinity testing with AR, and 5αRII.

2

Computed molecular electrostatic potential (MEP) maps of SARMs using an M06L/def2-SVP theoretical model, represented in electron volts (eV). Areas with more negative values (red) indicate higher susceptibility to nucleophilic attack, while areas with more positive values (blue) indicate higher susceptibility to electrophilic attack. The SARMs analyzed are represented in (A) GTX-024; (B) LGD-4033; (C) RAD-140; (D) S-4; (E) S-23; (F) S-101479; (G) Sarm2f; (H) YK11.

3

Analysis of the most reactive cavities (CAV) in different AR species (A–C), with data obtained using the CavityPlus Web server. Molecular docking was used to analyze potential affinity between the identified cavities in each AR species and SARMs (D–F), with data obtained through AutoDockVina and Discovery Studio Visualizer.

4

Analysis of the most reactive cavities (CAV) in different 5αRII species (A–B), with data obtained using the CavityPlus Web server. Molecular docking was used to analyze potential affinity between the identified cavities in each 5αRII species and SARMs (C–D), with data obtained through AutoDockVina and Discovery Studio Visualizer.

5

Interaction between AR (CAV1) with SARMs on molecular docking studies. (A) DHT-AR complex; (B) GTX-024-AR complex; (C) LGD-4033-AR complex; (D) RAD-140-AR; (E) S-4-AR complex; (F) S-23-AR complex; (G) S-102479-AR complex; (H) Sarm2f-AR complex; (I) YK11-AR complex. Data obtained using the software AutoDockVina, AutoDockTools and Discovery Studio Visualizer.

6

Interaction between 5αRII (CAV1) with SARMs on molecular docking studies. (A) Testosterone-5αRII complex; (B) Finasteride-5αRII complex (C) GTX-024–5αRII complex; (D) LGD-4033–5αRII complex; (E) RAD-140–5αRII; (F) S-4–5αRII complex; (G) S-23–5αRII complex; (H) S-102479–5αRII complex; (I) Sarm2f-5αRII complex; (J) YK11–5αRII complex. Data obtained using the software AutoDockVina, AutoDockTools and Discovery Studio Visualizer.

7

Molecular dynamics simulation of the backbone for the complexes between SARMs-AR over 50 ns, represented by (A) Radius of Gyration (R _g) trajectories; (B) Solvent Accessible Surface Area (SASA) trajectories; (C) Root-Mean-Square Deviation (RMSD) plots; (D) Root Mean Square Fluctuation (RMSF) plots; (E) The spatial arrangement of key residues in AR function, along with the distances between the backbone structures and these residues (scatter dot plot).

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Molecular dynamics simulation of the backbone for the complexes between SARMs-5αRII over 50 ns, represented by (A) Radius of Gyration (R _g) trajectories; (B) Solvent Accessible Surface Area (SASA) trajectories; (C) Root-Mean-Square Deviation (RMSD) plots; (D) Root Mean Square Fluctuation (RMSF) plots; (E) The spatial arrangement of key residues in 5αRII function, along with the distances between the backbone structures and these residues (scatter dot plot).

9

Scatter plots of the first two principal components (PC1 and PC2) thought time frame in nanoseconds. The plots represent the molecular dynamics over 50 ns for the following complexes: (A) DHT-AR, (B) Sarm2f-AR, (C) YK11-AR, (D) Finasteride-5αRII, (E) Sarm2f-5αRII, (F) Sarm2f-5αRII.