Identification of sodium alendronate derivatives as purple acid phosphatase inhibitors and promising candidates for osteoporosis therapeutics: in silico studies

Purple acid phosphatases (PAPs) belong to binuclear metallohydrolases which catalyze the hydrolysis of a variety of phosphorylated substrates at acidic to neutral pH. In humans, increasing PAP levels shows the progression of osteoporosis. Alendronate sodium is used to treat bone diseases. In this research, we designed and synthesized alendronate sodium derivatives for the first time, as specific inhibitors against the rkbPAP enzyme. Due to its ability to predict the binding site and binding a nity of ligands to receptors, molecular docking simulation is one of the most frequently used methods in Structure-Based Drug Design (SBDD). The three-dimensional structure of PAP (PDB ID: ۲QFR) was used for docking studies. Water molecules were removed from all coordinate files prior to docking, then minimized by chimera ۱.۱۶ software. The structure of compounds was constructed by ChemDraw v.۱۷.۳ and optimized using MM۲ calculation available in ChemBio۳D ۱۷.۳. Blind molecular docking analysis was planned. The grid box space was set on the whole space around the protein’s structures (PAP ۶۶×۴۶×۵۴˚A and grid-point spacing of ۱˚A). computational docking experiments were carried out by utilizing AutoDockVina v.۱.۱.۲. The docking results were analyzed using PyMOL, Discovery studio client, and Ligplot+ v.۲.۲.۷ software. The results indicated that all the docked compounds (۱-۹) interact with the enzyme by di↵erent binding a nity energies (in the range of ۶ to ۷kcal/mol). According to the the enzyme-ligand complexes, C۱۲H۱۸NNaO۹P۲ showed the highest binding a nity energy (-۷ kcal/mol) to interact with the enzyme, involved in hydrogen bond interactions with G۱۵۶, R۱۸۸, S۱۸۹, and Q۱۹۳ and hydrophobic interactions with T۱۱۸, Y۱۲۸, I۱۱۷, Q۱۵۷, Y۱۹۲, E۱۵۰, Y۱۴۹, and K۱۵۵. According to in silico studies C۱۱H۱۵N۲NaO۱۰P۲ were capable of interacting with His۲۰۲ and Asn۲۰۱, as critical residues involved in enzyme activity. so these compounds could be a candidate for the development of chemotherapeutics to treat osteoporosis

کلیدواژه ها:

Molecular docking ، Purple acid phosphatases ، alendronate sodium derivatives ، Osteoporosis ، Enzyme inhibitors