Synthesis of Thiourea Derivatives as Bioisosteric Structures of SERMs Pursuant to Virtual Screening

Dr. R Sundhararajan., J. Seraphine Joyce* , R. Abdul Basith,

K. Kalaiyarasi. , P. Manju, R .Vishnu Maaliga., A.Zainab Shaheen

Mohamed Sathak AJ College of Pharmacy, Sholinganallur, Chennai-600119

*Correspondence: theresa_sera@yahoo.com

DOI: https://doi.org/10.71431/IJRPAS.2026.5302    

INTRODUCTION   

Selective estrogen receptor modulators (SERMs) are non-steroidal compounds capable of exerting tissue-specific estrogen agonist or antagonist effects by differentially modulating ERα and ERβ. In the management of PCOS-associated infertility, SERMs such as Clomiphene citrate have been widely employed as first-line agents for ovulation induction. Bioisosterism represents a fundamental principle in medicinal chemistry aimed at improving biological activity and pharmacokinetic properties through the replacement of functional groups with structurally or electronically similar moieties. Thiourea derivatives have attracted increasing attention as valuable bioisosteric motifs in drug design due to their versatile chemical properties, including strong hydrogen-bonding capacity, conformational flexibility, and favorable electronic characteristics. The thiourea functional group (–NH–C(=S)–NH–) can serve as a bioisosteric replacement for urea, amide, or other heteroatom-containing linkers commonly present in classical SERMs.

The integration of bioisosteric design strategies with Thio-urea chemistry therefore represents a promising approach for the development of next-generation SERMs targeting PCOS-related infertility. Such compounds may overcome the limitations of existing therapies by offering enhanced efficacy, reduced resistance, and improved safety. Incorporation of Thio-urea moieties into SERM frameworks has the potential to enhance ligand–receptor interactions within the estrogen receptor binding domain, thereby improving affinity and selectivity toward ER subtypes involved in ovarian function.

                                                                      Fig .1

MECHANISM OF SERMs

             It was considered that there were two ways to inhibit / modulate estrogen action in Estrogen   Receptor (ER)

a.       competitively block the binding of endogenous agonists (estrogens) with “anti-estrogens”

b.      limit the production of “estrogens” using aromatase inhibitors.

However, this work focuses on the development of tissue selective estrogens intended to use for the prevention/treatment of osteoporosis as well as to deal with issues of PCOS

              It was observed, that different ER ligands acting through the same receptor could induce different transcriptional/functional responses in cells ^[1].

              Exploring the molecular basis for the observation,  “functional allostery” was developed which posits that the conformation of ER is influenced by the structure of the ligand with which it binds and that the shape of the ER-ligand complex predicts pharmacological activity (fig.1) This showed that “shape matters” as it enables the receptor to interact in a differential manner with functionally distinct coregulators (fig.2) resulting in different pharmacological responses ^[2].

Fig .2

MATERIALS AND METHODS

In this study, we used a range of bio-informatics tools to carry out the in-silico work. In our present investigation, we employed the following offline tools: Protein-ligand interaction profile (PLIP), PDB, the PubChem database, SPDBV, and Swiss Dock for molecular docking investigations. For molecular sketching, we also utilized Marvin Sketch.

Preparation of Protein

We acquired the targeted protein, the human estrogen receptor (PDB ID: A1AM4), from the PDB website. The protein preparation method began with the removal of water molecules, and then we added the missing H-atoms, ionization, and energy minimization of proteins. The Ramachandran plot was used to validate the energy reduction, which was accomplished by applying force using SPDBV software.

Active Site Identification

Following protein production, the protein-ligand interaction profile was used to determine which active amino acid was present in the protein's structure. We identified the protein's active amino acid residue using PLIP. Ligand Preparation Marvin Sketch program was used to sketch the 2D and 3D structures of the designed variants. After optimization, the sketched molecules are saved in the.pdb format for additional processing. Docking of Molecules The docking procedure was carried out using the Swiss Doc program.

Table 1. PDB file of A1AM4 (Estrogen receptor alpha ligand)