64 Infectious Disorders – Drug Targets, 2011, 11, 64-93 1871-5265/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. Development of Anti-Viral Agents Using Molecular Modeling and Virtual Screening Techniques Johannes Kirchmair 1,2 , Simona Distinto 1,2 , Klaus Roman Liedl 3 , Patrick Markt 1 Judith Maria Rollinger 4 , Daniela Schuster 1 , Gudrun Maria Spitzer 3 , and Gerhard Wolber 1,2, * 1 Department of Pharmaceutical Chemistry, Faculty of Chemistry and Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria; 2 Freie Universitaet Berlin, Institute of Phar- macy, Department Pharmaceutical Chemistry, Koenigin-Luisestrasse 2+4, 14195 Berlin, Germany; 3 Institute of Theo- retical Chemistry, Faculty of Chemistry and Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria; 4 Department of Pharmacognosy, Faculty of Chemistry and Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria Abstract: Computational chemistry has always played a key role in anti-viral drug development. The challenges and the quickly rising public interest when a virus is becoming a threat has significantly influenced computational drug discovery. The most obvious example is anti-AIDS research, where HIV protease and reverse transcriptase have triggered enormous efforts in developing and improving computational methods. Methods applied to anti-viral research include (i) ligand- based approaches that rely on known active compounds to extrapolate biological activity, such as machine learning tech- niques or classical QSAR, (ii) structure-based methods that rely on an experimentally determined 3D structure of the tar- gets, such as molecular docking or molecular dynamics, and (iii) universal approaches that can be applied in a structure- or ligand-based way, such as 3D QSAR or 3D pharmacophore elucidation. In this review we summarize these molecular modeling approaches as they were applied to fight anti-viral diseases and highlight their importance for anti-viral re- search. We discuss the role of computational chemistry in the development of small molecules as agents against HIV inte- grase, HIV-1 protease, HIV-1 reverse transcriptase, the influenza virus M2 channel protein, influenza virus neuramini- dase, the SARS coronavirus main proteinase and spike protein, thymidine kinases of herpes viruses, hepatitis C virus pro- teins and other flaviviruses as well as human rhinovirus coat protein and proteases, and other picornaviridae. We highlight how computational approaches have helped in discovering anti-viral activities of natural products and give an overview on polypharmacology approaches that help to optimize drugs against several viruses or help to optimize the metabolic profile of and anti-viral drug. Keywords: Activity profiling, computational chemistry, docking, drugs from natural sources, fingerprints, HCV NS3/4A serine protease, HCV NS5B RNA-dependent RNA-polymerase, hepatitis C virus, herpes, HIV, HIV integrase, HIV-1 protease, HIV-1 reverse transcriptase, homology modeling, HRV capsid protein, HRV protease 2A, HRV protease 3C, HSV, human - glucosidase, influenza virus, inverse screening, lead structure development, M2 channel protein, molecular dynamics simula- tion, molecular interaction fields, molecular modeling, natural compounds, neuraminidase, parallel screening, pharmacophore modeling, QSAR, SARS-CoV, similarity-based screening, thymidine kinase, viral disease, virtual screening, virus. INTRODUCTION Viral diseases represent a major threat to human health. Examples of clinically highly important viruses include the influenza, HIV (human immunodeficiency virus), SARS- CoV (severe acute respiratory syndrome coronavirus), HCV (hepatitis C virus), VZV (varicella-zoster virus), HCMV (human cytomegalovirus), HRV (human rhino virus), and herpes simplex (HSV). From the 15 th through the 19 th centu- ries, the Europeans imported communicable diseases such as smallpox (variola viruses) and measles (a morbilivirus) to America. Lacking immunity to these “new” viral diseases, the outcome of these epidemics was devastating for entire native populations [1]. Smallpox in particular accelerated the fall of Native Americans and played into the hands of the Europeans in their efforts to repress them. The Spanish flu *Address correspondence to this author at the Freie Universitaet Berlin, Institute of Pharmacy, Department Pharmaceutical Chemistry, Koenigin- Luisestrasse 2+4, 14195 Berlin, Germany; Tel: +49 30 838 52686, Fax: +49 30 838 56206; E-mail: wolber@zedat.fu-berlin.de (influenza virus) pandemic is rightly named the mother of all pandemics and illustrates the global health threat and dam- age that emerges from highly virulent viruses [2]. Between 1918 and 1919, the Spanish flu caused an estimated death toll of 40-50 million people [3, 4]. The pandemic was caused by direct transmission of the highly virulent H1N1 serotype from birds to humans [5]. Since its first description in homosexual men in San Francisco, USA, HIV has become one of the most devastat- ive epidemics in recent history, causing 2 million deaths re- lated to this viral disease in 2007. HIV prevalence is particu- larly high in sub-Saharan Africa, with highest rates in Swazi- land for both females (23%) and males (6%). Though preva- lence could be stabilized in recent years, the number of peo- ple living with HIV is still increasing due to ongoing new infections and increasing access to anti-viral therapy [6]. However, also viruses bearing low risks for humans, e.g., viral respiratory infections, are causing an enormous eco- nomic burden [7].