787 Journal of Biomolecular Structure & Dynamics, ISSN 0739-1102 Volume 28, Issue Number 5, (2011) ©Adenine Press (2011) Using Computer-aided Drug Design and Medicinal Chemistry Strategies in the Fight Against Diabetes http://www.jbsdonline.com Abstract The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibi- tor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predic- tions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith. Key words: Diabetes; Drug design; DPP-IV inhibitors. Introduction Diabetes is one of the most important diseases of our time, with an increas- ing reported worldwide incidence (1-3). The most important incretin hormones identified are the gastric inhibitory polypeptide (GIP) and the glucagon-like peptide-1 (GLP-1), which are quickly inactivated in circulation by the enzyme dipeptidyl peptidase IV (DPP-IV), a serine peptidase (4-7). Inhibition of DPP-IV prevents GLP-1 and GIP degradation and can reduce glucose levels in diabetics. DPP-IV is involved in intracellular signaling, metabolism and acti- vation of peptides, including GIP, insulin-like growth factors, endomorphin, enterostatin. Most of the DPP-IV protein is extracellular, with a hydrophobic transmembrane sequence (amino acids 7-28) anchoring the protein in the cell membrane. The catalytic region encompasses amino acids 511-576. The wide tissue distribution of DPP-IV on numerous cell types and vascular beds as well as its presence as a soluble active enzyme in the circulation ensures that DPP- IV-mediated proteolysis is a common event in most tissue compartments. Thus, DPP-IV inhibition has been proposed as a new treatment of type 2 diabetes (8, 9), and after the discovery of GLP-1, DPP-IV inhibition became a major research target. An increasing number of theoretical research have recently investigated diseases such as cancer, AIDS and others, emphasizing therapeutic targets as well as inhibitors (10-12). The aim of this work is to present a practical sequence of steps or protocol toward a rational design of novel DPP-IV inhibitors for Diabetes therapy. *Phone: 55 16 3602 4717 55 21 2141 7201 E-mail: tomich@fcfrp.usp.br catff@terra.com.br Evandro P. Semighini 1 Jonathan A. Resende 1 Peterson de Andrade 1 Pedro A. B. Morais 1 Ivone Carvalho 1 Carlton A. Taft 2 * Carlos H. T. P. Silva 1 * 1 Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Monte Alegre, 14040-903, Ribeirão Preto-SP, Brazil 2 Centro Brasileiro de Pesquisas Físicas, Rua Dr. Xavier Sigaud, 150, Urca, 22290-180, Rio de Janeiro-RJ, Brazil