Molecular Dynamics (MD) Simulation of GPR87-LPA Binding: Therapeutic Implications for Targeted Cancer Treatment.

Abstract

GPR87 is an orphan G-protein-coupled receptor (GPCR) that represents a potential molecular target for developing novel drugs aimed at treating Squamous Cell Carcinomas (SCCs) or adenocarcinomas of the lungs and bladder. The aim of the present research is to screen a variety of LPA analogues using computational methods to identify the most promising inhibitors of the GPR87 protein. Further, the objective of this study was to construct the structure of the human GPR87 protein using two template- based tools, Phyre2 and SWISS-MODEL, alongside the Iterative Threading Assembly Refinement (ITASSER) server. Additionally, neural network-based de novo modeling approaches, such as AlphaFold2, were utilized. The resulting GPR87 structure was validated by comparing it with the structural properties of the templates using the Verify-3D, ProSA, and ERRAT servers. We conducted a comprehensive structural and functional analysis of the target protein using various computational tools. Several computational techniques were employed to explore the structural and functional characteristics of the target, with LPA selected as the initial pharmacological candidate. A library of 2,605 LPA analogues was screened against orphan GPR87 through in-silico docking analysis to identify higher-affinity and more selective potential drugs. Molecular Dynamics (MD) simulations were performed to track structural changes and convergence during the simulations. Key metrics, including the root mean square fluctuation (RMSF) of Cα-atoms, the radius of gyration, and the RMSD of backbone atoms, were calculated for both the apo-form and the LPA-GPR87 complex structures. These studies on structure-based drug targeting could pave the way for the development of specific inhibitors for the treatment of squamous cell carcinomas, and the findings may contribute to the design and development of new therapeutic compounds targeting GPR87 for the treatment of SCC.