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Plenary Lecture

Rational Biomimetic Drug Discovery; A Computer-Aided Drug Design Based on µ and ω Conotoxins

Professor Babak Khalili Hadad
Department of Biological Sciences
Islamic Azad University - Roudehen Branch
IRAN
E-mail: khalili@riau.ac.ir

Abstract: Cone snail toxins called Conotoxins; function as selective modulators of voltage-gated channels. These peptides act selectively at a wide range of G-protein coupled receptors, cell membranes transporters and ion channels. This potential makes them great interest for protein based rational drug synthesis. Malfunction of voltage-gated channels which have electrophysiological importance associated with some neuromuscular and cardiovascular diseases including epilepsy and long QT syndrome. Consequently development of drugs based on Conotoxins can be helpful for treatment. The subtypes Voltage-gated sodium channels (VGSCs) are classified to Nav1.1 to Nav1.9 based on their inhibition by toxins which can control the influx of sodium ions. They have different physiologic roles e.g. Nav1.3, -1.7, -1.8, and -1.9 are involved in pain pathways. μ-conotoxins and ω-conotoxins, are two common standard drugs in neuroscience researches. The μ-conotoxins immobilize the skeletal muscles without affecting axonal or synaptic events. This family has the ability to block the muscle Na+ channel, Nav1.4. Axonal Na+ channels, Nav1.1– Nav1.3 and Nav1.6– Nav1.9 are not affected. The ω-conotoxins are used as reagents in voltage-gated calcium (Ca2+) channel and block neurotransmitter release. ω-conotoxins have also been used to diagnose the Ca2+ channel targeted disease, Lambert-Eaton myasthenic syndrome. In present study, some structures as inhibitor and modulator, based on conotoxins are suggested. To reach the new dugs the first task is to select a target protein. It is important to introduce the molecular biochemical function, completely. Having some chemicals with natural sources and known function will lead us to find more effective drugs, suitable to bind the protein tightly and be easy to synthesis or modification. To have real bio-accessibility, specificity and fewer side effects are considerable also. The steric and physicochemical complementarity of the binding site of protein and the protein based drug molecule is important. The extent of the evolutionary changes cause, the recognition of homology or orthology among proteins to be difficult, but it is helpful to expect on the sequence, structure and function level. Structural based drug design, molecular dynamics, ONIOM, QSAR as well as docking are the common tools to follow the processes. These aspects include the evaluation of affinity/specificity, hydrophilicity / lipophilicity, distribution, absorption, electrophilic, nucleophilic, and radical attack, biotransformation, which are discussed in this lecture, respectively. Most of these aspects could be performed initially using computational tools. In this presentation bioinformatics methods to predict the protein structure are described and their use towards the drug design is discussed.

Brief Biography of the Speaker: Babak Khalili Hadad graduated from Azad University- Sciences and Research Branch in Biochemistry, where he has started to combine Biomedical sciences with Bioinformatics to explain the mechanism of some diseases. Computer-aided drug design and delivery, docking and ligand- target protein interaction are among his interests. Before that he had graduated in Msc. degree of Clinical and applied Biochemistry from Kerman University of Medical Sciences, and B.Sc. of Cell and Molecular Biology, from Shiraz University of Sciences. He has started to teach Biochemistry (Advanced animal & plant metabolism, Control of metabolism, Pure and Clinical Enzymology, Clinical biochemistry, Bioinformatics) and Molecular biology since 1998. He has been in the organizing committee of some Bioinformatics congresses up to now and also, the editorial board member of American Journal of Bioinformatics Research. He has also been awarded several times as Top university professor and Top researcher. His research interests in Azad University, Faculty of Sciences - Roudehen Branch focus on Biochemical aspects of Bone diseases, specially, Heterotopic ossification and Scoliosis, Blood disorders and Hormonal malfunctions. He has 17 published papers and 3 submitted as well as 16 presentations in national and international congresses.

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