Development of novel anticancer agents targeting G protein coupled receptor: GPR120

The G-protein coupled receptor, GPR120, has ubiquitous expression and multifaceted roles in modulating metabolic and anti-inflammatory processes. GPR120 - also known as Free Fatty Acid Receptor 4 (FFAR4) is classified as a free fatty acid receptor of the Class A GPCR family. GPR120 has recently been implicated as a novel target for cancer management. GPR120 gene knockdown in breast cancer studies revealed a role of GPR120-induced chemoresistance in epirubicin and cisplatin-induced DNA damage in tumour cells. Higher expression and activation levels of GPR120 is also reported to promote tumour angiogenesis and cell migration in colorectal cancer. A number of agonists targeting GPR120 have been reported, such as TUG891 and Compound39, but to date development of small-molecule inhibitors of GPR120 is limited. This research applied a rational drug discovery approach to discover and design novel anticancer agents targeting the GPR120 receptor. A homology model of GPR120 (short isoform) was generated to identify potential anticancer compounds using a combined in silico docking-based virtual screening (DBVS), molecular dynamics (MD) assisted pharmacophore screenings, structure–activity relationships (SAR) and in vitro screening approach. A pharmacophore hypothesis was derived from analysis of 300 ns all-atomic MD simulations on apo, TUG891-bound and Compound39-bound GPR120 (short isoform) receptor models and was used to screen for ligands interacting with Trp277 and Asn313 of GPR120. Comparative analysis of 100 ns all-atomic MD simulations of 9 selected compounds predicted the effects of ligand binding on the stability of the “ionic lock” – a characteristic of Class A GPCRs activation and inactivation. The “ionic lock” between TM3(Arg136) and TM6(Asp) is known to prevent G-protein recruitment while GPCR agonist binding is coupled to outward movement of TM6 breaking the “ionic lock” which facilitates G-protein recruitment. The MD-assisted pharmacophore hypothesis predicted Cpd 9, (2-hydroxy-N-{4-[(6-hydroxy-2-methylpyrimidin-4-yl) amino] phenyl} benzamide) to act as a GPR120S antagonist which can be evaluated and characterised in future studies. Additionally, DBVS of a small molecule database (~350,000 synthetic chemical compounds) against the developed GPR120 (short isoform) model led to selection of the 13 hit molecules which were then tested in vitro to evaluate their cytotoxic, colony forming and cell migration activities against SW480 – human CRC cell line expressing GPR120. Two of the DBVS hit molecules showed significant (\u3e 90%) inhibitory effects on cell growth with micromolar affinities (at 100 μM) - AK-968/12713190 (dihydrospiro(benzo[h]quinazoline-5,1′-cyclopentane)-4(3H)-one) and AG-690/40104520 (fluoren-9-one). SAR analysis of these two test compounds led to the identification of more active compounds in cell-based cytotoxicity assays – AL-281/36997031 (IC50 = 5.89–6.715 μM), AL-281/36997034 (IC50 = 6.789 to 7.502 μM) and AP-845/40876799 (IC50 = 14.16-18.02 μM). In addition, AL-281/36997031 and AP-845/40876799 were found to be significantly target-specific during comparative cytotoxicity profiling in GPR120-silenced and GPR120-expressing SW480 cells. In wound healing assays, AL-281/36997031 was found to be the most active at 3 μM (IC25) and prevented cell migration. As well as in the assessment of the proliferation ability of a single cell to survive and form colonies through clonogenic assays, AL-281/36997031 was found to be the most potent of all three test compounds with the survival rate of ~ 30% at 3 μM. The inter-disciplinary approach applied in this work identified potential chemical scaffolds –spiral benzo-quinazoline and fluorenone, targeting GPR120 which can be further explored for designing anti-cancer drug development studies

Exploring the Role of Molecular Dynamics Simulations in Most Recent Cancer Research: Insights into Treatment Strategies

Cancer is a complex disease that is characterized by uncontrolled growth and division of cells. It involves a complex interplay between genetic and environmental factors that lead to the initiation and progression of tumors. Recent advances in molecular dynamics simulations have revolutionized our understanding of the molecular mechanisms underlying cancer initiation and progression. Molecular dynamics simulations enable researchers to study the behavior of biomolecules at an atomic level, providing insights into the dynamics and interactions of proteins, nucleic acids, and other molecules involved in cancer development. In this review paper, we provide an overview of the latest advances in molecular dynamics simulations of cancer cells. We will discuss the principles of molecular dynamics simulations and their applications in cancer research. We also explore the role of molecular dynamics simulations in understanding the interactions between cancer cells and their microenvironment, including signaling pathways, proteinprotein interactions, and other molecular processes involved in tumor initiation and progression. In addition, we highlight the current challenges and opportunities in this field and discuss the potential for developing more accurate and personalized simulations. Overall, this review paper aims to provide a comprehensive overview of the current state of molecular dynamics simulations in cancer research, with a focus on the molecular mechanisms underlying cancer initiation and progression.Comment: 49 pages, 2 figure

Class A Orphans in GtoPdb v.2021.3

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [161], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [121]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GRP65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119)