A mechanistic in silico molecular recognized approach for the ligand based generation of a dual N-formyl-Met-Leu-Phe (fMLP), and MMK-1peptide mimetic hyper-agonist fMLP targeted receptor against the PGE2 EP4 pathway chemotherapy-induced alopecia. Grigoriadis Ioannis1, Grigoriadis George2 and Grigoriadis Nikolaos3* 1.Department of Computer Drug Discovery Science, BiogenetoligandorolTM, Thessaloniki, Greece, 2.Department of Stem Cell Bank and ViroGeneaTM, Biogenea Pharmaceuticals Ltd, Thessaloniki, Greece, 3.Department of IT Computer Aided Personalized Myoncotherapy, Cartigenea-Cardiogenea, Neurogenea-Cellgenea, Cordigenea-HyperoligandorolTM, ABSTRACT: It has been shown that the Oral administration for 6 days of 100 mg/kg MMK-1, of an agonist peptide selective for the FPRL1 receptor, suppressed alopecia induced by the anticancer drug etoposide in neonatal rats. However, the anti-alopecia effect of orally administered MMK-1 was inhibited by indomethacin, an inhibitor of cyclooxygenase (COX), or AH-23848B, an antagonist of the EP4 receptor for prostaglandin (PG) E2, suggesting involvement of PGE2 release and the EP4 receptor in the oral MMK-1 anti-alopecia mechanism. The anti-alopecia effect of orally administered MMK-1 was also blocked by an inhibitor of nuclear factor-kappaB (NF- kappaB), pyrrolidine dithiocarbamate, suggesting that the oral anti-alopecia effect of MMK-1 may be mediated by activation of NF-kappaB. These results suggested that MMK-1 bound to FPRL1 receptor might suppress etoposide-induced apoptosis of hair follicle cells and alopecia by way of PGE2 release and NF-kappaB activation. Previously, it has also been found that an intraperitoneally administered chemotactic peptide, N-formyl-Met-Leu-Phe (fMLP), and MMK-1, a selective agonist of formyl peptide receptor-like 1 (FPRL1) receptor, the low affinity subtype of the fMLP receptor, prevented the alopecia in neonatal rats induced by the anticancer agent etoposide. The anti-alopecia effect of fMLP was not inhibited at all by Boc-FLFLF, a selective antagonist of formylpeptide receptor (FPR), which is the high affinity subtype of the receptor, but it was partly inhibited by Trp-Arg-Trp-Trp-Trp-Trp-NH(2) (WRW(4)), an antagonist of FPRL1 receptor. The anti-alopecia effects of fMLP and MMK- 1 were also inhibited by Lys-D-Pro-Thr (K(D)PT) and pyrrolidine dithiocarbamate, which are inhibitors of interleukin-1 (IL-1) and nuclear factor-kappaB (NF-kappaB) respectively. Computational methods utilizing the structural and functional information help to understand specific molecular recognition events between the target biomolecule and candidate hits and make it possible to design improved lead molecules for the target. Here we represents a massive on-going scientific endeavor to provide a freely accessible state of the art software suite for protein and DNA targeted lead molecule discovery. by resulting in a Mechanistic in silico molecular recognized approach for the ligand based generation of a dual N-formyl-Met-Leu-Phe (fMLP), and MMK-1peptide mimetic agonists formyl-peptide hyper-agonist interactive receptors against chemotherapy-induced alopecia. II METHODS Α Sequential Solution of the Poisson-Boltzmann Equation through a Combination Index Dynamic Unified Theorem for Multiple Entities: and when m ≠ 1, then: Based on Eqs. 1 and 2, in conjunction with Eq. 4, Chou and Talalay in 1983 introduced the term combination index (CI) for quantification of synergism (CI<1), additive effect (CI=1), and antagonism (CI>1) [6,13,14], where at x% inhibition, the general equation for two drugs is given below: A typical presentation of algorithms and graphics of CI values as a function of effect (fa) is illustrated in Figure 2. The resulting Fa-CI plot is also called Chou-Talalay plot. The Fa-CI plot and isobologram are two sides of the same coin, where Fa-CI plot is effect-oriented and the isobologram is dose-oriented (Figure 1). More details have been given in Reference 6. The algorithm for