AI-based 3D-QSAR model of FDA-approved repurposed drugs for inhibiting sclerostin

Article type: Research Article

Authors: Yadalam, Pradeep Kumar^a | Anegundi, Raghavendra Vamsi^a | Ramadoss, Ramya^{b; *} | Shrivastava, Deepti^{c; *} | Almufarrij, Raha Ahmed Shamikh^d | Srivastava, Kumar Chandan^{e; f}

Affiliations: [a] Department of Periodontics, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India | [b] Department of Oral Biology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India | [c] Preventive Dentistry Department, Periodontics Division, College of Dentistry, Jouf University, Sakaka, Saudi Arabia | [d] College of Dentistry, Jouf University, Sakaka, Saudi Arabia | [e] Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Oral Medicine and Maxillofacial Radiology Division, College of Dentistry, Jouf University, Sakaka, Saudi Arabia | [f] Department of Oral Medicine and Radiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India

Correspondence: [*] Corresponding authors: Ramya Ramadoss, Department of Oral Biology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India. E-mail: [email protected]. Deepti Shrivastava, Periodontics Division, Preventive Dentistry Department, College of Dentistry, Jouf University, Sakaka, 72345, Saudi Arabia. Tel.: +966 500782498; E-mail: [email protected].

Abstract: BACKGROUND: Wnt activation promotes bone formation and prevents bone loss. The Wnt pathway antagonist sclerostin and additional anti-sclerostin antibodies were discovered as a result of the development of the monoclonal antibody romosozumab. These monoclonal antibodies greatly increase the risk of cardiac arrest. Three-dimensional quantitative structure-activity relationships (3D-QSAR) predicts biological activities of ligands based on their three-dimensional features by employing powerful chemometric investigations such as artificial neural networks (ANNs) and partial least squares (PLS). OBJECTIVE: In this study, ligand-receptor interactions were investigated using 3D-QSAR Comparative molecular field analysis (CoMFA). Estimates of steric and electrostatic characteristics in CoMFA are made using Lennard-Jones and Coulomb potentials. METHODS: To identify the conditions necessary for the activity of these molecules, fifty Food and Drug Administration (FDA)-approved medications were chosen for 3D-QSAR investigations and done by CoMFA. For QSAR analysis, there are numerous tools available. This study employed Open 3D-QSAR for analysis due to its simplicity of use and capacity to produce trustworthy results. Four tools were used for the analysis on this platform: Py-MolEdit, Py-ConfSearch, and Py-CoMFA. RESULTS: Maps that were generated were used to determine the screen’s r2 (Coefficient of Multiple Determinations) value and q2 (correlation coefficient). These numbers must be fewer than 1, suggesting a good, trustworthy model. Cross-validated (q2) 0.532 and conventional (r2) correlation values of 0.969 made the CoMFA model statistically significant. The model showed that hydroxamic acid inhibitors are significantly more sensitive to the steric field than the electrostatic field (70%) (30%). This hypothesis states that steric (43.1%), electrostatic (26.4%), and hydrophobic (20.3%) qualities were important in the design of sclerostin inhibitors. CONCLUSION: With 3D-QSAR and CoMFA, statistically meaningful models were constructed to predict ligand inhibitory effects. The test set demonstrated the model’s robustness. This research may aid in the development of more effective sclerostin inhibitors that are synthesised using FDA-approved medications.

Keywords: 3dQSAR, sclerostin, bone formation

DOI: 10.3233/THC-231358

Journal: Technology and Health Care, vol. 32, no. 5, pp. 3007-3019, 2024