Protein-Ligand Based Pharmacophore Approach against ERK5 Involved in Breast Cancer; In-Silico Study of Flavonoids from Blighia sapida

Abstract Conclusions: Flavonoids from B. sapida may serve as promising inhibitors of ERK5 for breast cancer management. Background: Breast cancer is a global public health issue that can be caused by environmental or hereditary factors. There are still a shortage of effective treatments with enhanced efficacy and acceptability against the disease, as many breast cancer drugs have serious side effects. Hence, the inhibitory potential of flavonoids from Blighia sapida against breast cancer target (ERK5) was investigated. The interactions of the target protein and its co-crystallized ligand were used to develop a protein-ligand based pharmacophore hypothesis. The idea was applied to the screening of phytochemicals obtained from an online database. Following that, we used structural bioinformatics and theoretical chemistry tools to find new ERK5 inhibitors using molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) and pharmacokinetics model in Schrödinger suite, density functional theory analysis (DFT) was also performed using Spartan 10. Results: The technique discovered new lead molecules as inhibitors of ERK5 as breast cancer therapy through molecular docking and MM/GBSA calculation with Quercetin, Kaempferol and (+)-Catechin showing higher docking score than the co-cystalized ligand and the standard drug. In the phase-generated E-pharmacophore theory, the postulated pharmacophore hypothesis has a hydrogen bond acceptor, hydrogen bond donor, and aromatic ring. Interestingly, all the hits obeyed Lipinski rule of five. The results of the frontier molecular orbitals revealed that the EHOMO values of the hit compounds range from -6.02 to -5.48 eV indicating that all the hit compounds will readily donate electron. Conclusions: Flavonoids from B. sapida may serve as promising inhibitors of ERK5 for breast cancer management.