Discovery of Novel RARα Agonists Using Pharmacophore-based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Studies
Atefeh Ghorayshian, Mahshid Danesh, Tahereh Mostashari-Rad, Afshin fassihi
Abstract
Nuclear retinoic acid receptors (RARs) are ligand-dependent transcription factors involved in various biological processes, such as embryogenesis, cell proliferation, differentiation, reproduction, and apoptosis. These receptors are regulated by retinoids, i.e., retinoic acid (RA) and its analogs, as receptor agonists. RAR agonists are promising therapeutic agents for the treatment of serious dermatological disorders, including some malignant conditions. By inducing apoptosis, they are able to inhibit the proliferation of diverse cancer cell lines. Also, RAR agonists have recently been identified as therapeutic options for some neurodegenerative diseases. These features make retinoids very attractive molecules for medical purposes. Synthetic selective RAR agonists have several advantages over endogenous ones, but they suffer poor pharmacokinetic properties. These compounds are normally lipophilic acids with unfavorable drug-like features such as poor oral bioavailability. Recently, highly selective, potent, and less toxic RAR agonists with proper lipophilicity, thus, good oral bioavailability have been developed for some therapeutic applications. In the present study, ligand and structure-based virtual screening technique was exploited to introduce some novel RARα agonists. Pharmacokinetic assessment was also performed in silico to suggest those compounds which have optimized drug-like features. Finally, two compounds with the best in silico pharmacological features are proposed as lead molecules for future development of RARα agonists.
Introduction
Retinoic acid (RA), one of the primary active metabolites of vitamin A (retinol), is involved in regulating various biological processes such as immune responses, embryogenesis, homeostasis, cell proliferation, differentiation, apoptosis, and organogenesis [1, 2]. RA exists as at least six isomers (all-trans, all-trans-4-oxo, 9-cis, 9-cis-4-oxo, 13-cis, 13-cis-4-oxo) among them, all-trans-RA (ATRA) and 9-cis-RA (9cRA) are the most potent biologically active forms [3]. The conversion of ATRA into 9cRA and other isomers (as a reversible process) generates biological-active RA derivatives [4]. RAs or, more generally, retinoids exert their biological effects by binding as agonists to specific nuclear receptors called RA receptors (RARs) which exist in different types [5].
Methods
In this research, a well-established protocol of virtual screening was applied to find some novel activators of retinoic acid receptor type α. In the first step of this procedure, a pharmacophore was constructed based on the interaction of RAR568, a selective activator of RARα with this receptor. In the second step, ten different databases were subjected to search for compounds with structural similarity to this pharmacophore. Pharmacokinetics and pharmacodynamics features of the obtained structures were evaluated in order to filter off more potent and drug-like compounds. Finally, compounds with proper in silico pharmacologic were subjected to more detailed investigation of ligand-receptor interactions.
Results
Pharmacophore search
A pharmacophore is an ensemble of molecular structure features, i.e., hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic centroids (HYP), aromatic rings (Aro), positive ions (PI), and negative ions (NI). They are all crucial for molecular recognition of a given ligand by a specific biological macromolecule to trigger (or block) its biological response [76, 77]. A pharmacophore model may be applied to identify hit molecules with similar structural features against the binding site of the macromolecule target [78]. Pharmacophore search was carried out using Pharmit web server based on the pharmacophore features and molecular shape of RAR568. Moreover, the key interactions of RAR568 with amino acid residues at the binding site of RARα were investigated to identify pharmacophore hits via specific electronic and steric properties at various geometrical orientations responsible for the molecular activity [79, 80].
Discussion
Analysis of binding free energies for RARα complex structures
MM-PBSA approach was carried out for calculating the binding energies of RARα in complex with RAR568 and the five selected compounds (Table 2). The results provided more information about the interaction mechanisms between RARα and agonist candidates (Fig 11). The best binding affinities were obtained for compounds 1 and 2 (compared with RAR568) with -44.6633 kcal.mol-1 and -35.5151 kcal.mol-1, respectively. This finding was in agreement with the docking results. According to MM-PBSA results, Van der Waals interactions had a critical role in binding affinities that were greater in compounds 1 and 2 compared with the other compounds. These findings are also corroborated by the literature [110, 111]. However, electrostatic interactions also played a decisive role in binding compounds to RARα. RAR568 and compound 4 showed the same binding affinities (-33 kcal.mol-1), and the lowest binding affinity was observed for compounds 11 and 8 with -29.6729 and -31.2386 kcal.mol-1, respectively.
Conclusion
Retinoids play crucial roles in regulating various biological processes due to their specific effects on cell proliferation, differentiation, and apoptosis. This makes them very attractive molecules for medical purposes. Retinoids exert their biological effects through binding to the nuclear retinoic acid receptors. Adverse effects restrict the further development and clinical application of these therapeutic agents. The ultimate goal of the present study was to introduce some potent and novel RARα-selective agonists with good drug-like features based on the RAR568 pharmacophore properties. Initially, pharmacophore search along with ADMET assessments and Virtual Screening were performed to generate a potential collection of RARα agonist candidates.
Citation: Ghorayshian A, Danesh M, Mostashari-Rad T, fassihi A (2023) Discovery of novel RARα agonists using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulation studies. PLoS ONE 18(8): e0289046. https://doi.org/10.1371/journal.pone.0289046
Editor: Sheikh Arslan Sehgal, The Islamia University of Bahawalpur Pakistan, PAKISTAN
Received: September 15, 2022; Accepted: July 10, 2023; Published: August 24, 2023
Copyright: © 2023 Ghorayshian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0289046#abstract0
