Comparative modeling and virtual screening for the identification of novel inhibitors for myo-inositol-1-phosphate synthase Syed Sikander Azam • Sara Sarfaraz • Asma Abro Received: 24 May 2013 / Accepted: 5 April 2014 Ó Springer Science+Business Media Dordrecht 2014 Abstract Myo-inositol-1-phosphate (MIP) synthase is a key enzyme in the myo-inositol biosynthesis pathway. Disruption of the inositol signaling pathway is associated with bipolar disorders. Previous work suggested that MIP synthase could be an attractive target for the development of anti-bipolar drugs. Inhibition of this enzyme could possibly help in reducing the risk of a disease in patients. With this objective, three dimensional structure of the protein was modeled followed by the active site prediction. For the first time, computational studies were carried out to obtain structural insights into the interactive behavior of this enzyme with ligands. Virtual screening was carried out using FILTER, ROCS and EON modules of the OpenEye scientific software. Natural products from the ZINC data- base were used for the screening process. Resulting com- pounds were docked into active site of the target protein using FRED (Fast Rigid Exhaustive Docking) and GOLD (Genetic Optimization for Ligand Docking) docking pro- grams. The analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a sig- nificant role in ligand binding. Four compounds are shortlisted and their binding assay analysis is underway. Keywords Myo-inositol-1-phosphate synthase  Myo-inositol  Bipolar disorder  Virtual screening  Docking Introduction Myo-inositol forms backbone of many cellular compounds, most of which are involved in signaling pathways. Inositol is an essential component of structural lipids [1]. Phosphory- lated inositol derivatives, both membrane bound and water soluble inositol phosphates, play a vital role in signaling pathways; regulating many cellular processes including chromatin remodeling, DNA repair, transcription, and cell wall synthesis [2, 3]. Myo-inositol is a key part of the second messenger system. In mammalian brain, the inositol sig- naling serves as a major pathway linking various receptor systems of the central nervous system. These include sero- tonergic, muscarinic, adrenergic, histaminergic, metabo- tropic, neurotensin, and platelet activating factor receptor systems [4]. Myo-inositol, a substrate for the synthesis of membrane lipid phosphatidylinositol (PtdIns), is synthe- sized from glucose-6-phosphate (G-6-P) in two steps. The first step is catalyzed by inositol-3-phosphate synthase also known as myo-inositol-1-phosphate synthase (MIP syn- thase) (EC 5.5.1.4). MIP synthase is an important enzyme in myo-inositol biosynthesis pathway. The enzyme converts D- glucose 6-phosphate to 1D-myo-inositol-3-phosphate in NAD dependent manner, the first committed step in the production of all inositol-containing compounds, including phospholipids. It is a rate-limiting enzyme in the synthesis of all inositol-containing compounds [5]. MIP synthase is an isomerase that belongs to a class of intramolecular lyases. It is highly expressed in reproductive organs, heart, placenta and pancreas while weakly expressed in white blood cells, thymus, skeletal muscle and colon [6]. The enzyme remains highly conserved over evolutionary time and exists in cytoplasmic form. Defective neuronal inositol phosphate signaling leads to bipolar disorder [7–9]. It is a severe psychiatric illness Electronic supplementary material The online version of this article (doi:10.1007/s11033-014-3370-8) contains supplementary material, which is available to authorized users. S. S. Azam (&)  S. Sarfaraz  A. Abro National Center for Bioinformatics, Quaid-i-Azam University, Islamabad 45320, Pakistan e-mail: ssazam@qau.edu.pk; syedazam2008@gmail.com 123 Mol Biol Rep DOI 10.1007/s11033-014-3370-8