molecules Molecular Modeling in Drug Design Edited by Rebecca C. Wade and Outi M. H. Salo-Ahen Printed Edition of the Special Issue Published in Molecules www.mdpi.com/journal/molecules Molecular Modeling in Drug Design Molecular Modeling in Drug Design Special Issue Editors Rebecca C. Wade Outi M. H. Salo-Ahen MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Rebecca C. Wade Outi M. H. Salo-Ahen HITS gGmbH/Heidelberg University Abo˚ Akademi University Germany Finland Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) from 2018 to 2019 (available at: https://www.mdpi.com/journal/molecules/ special issues/MMDD) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-614-1 (Pbk) ISBN 978-3-03897-615-8 (PDF) c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ..................................... vii Preface to ”Molecular Modeling in Drug Design” ........................... ix Rebecca C. Wade and Outi M. H. Salo-Ahen Molecular Modeling in Drug Design Reprinted from: Molecules 2019, 24, 321, doi:10.3390/molecules24020321 .............. 1 Ruyin Cao, Alejandro Giorgetti, Andreas Bauer, Bernd Neumaier, Giulia Rossetti and Paolo Carloni Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study Reprinted from: Molecules 2018, 23, 2616, doi:10.3390/molecules23102616 .............. 4 Maksim Kouza, Anirban Banerji, Andrzej Kolinski, Irina Buhimschi and Andrzej Kloczkowski Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes Reprinted from: Molecules 2018, 23, 1995, doi:10.3390/molecules23081995 .............. 21 Francesco Tavanti, Alfonso Pedone and Maria Cristina Menziani Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1–40) Fibrils Reprinted from: Molecules 2018, 23, 1320, doi:10.3390/molecules23061320 .............. 31 Lucas A. Defelipe, Juan Pablo Arcon, Carlos P. Modenutti, Marcelo A. Marti, Adri´an G. Turjanski and Xavier Barril Solvents to Fragments to Drugs: MD Applications in Drug Design Reprinted from: Molecules 2018, 23, 3269, doi:10.3390/molecules23123269 .............. 46 Yankun Chen, Xi Chen, Ganggang Luo, Xu Zhang, Fang Lu, Liansheng Qiao, Wenjing He, Gongyu Li and Yanling Zhang Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect Reprinted from: Molecules 2018, 23, 1040, doi:10.3390/molecules23051040 .............. 60 Lucas G. Viviani, Erika Piccirillo, Arquimedes Cheffer, Leandro de Rezende, Henning Ulrich, Ana Maria Carmona-Ribeiro and Antonia T.-do Amaral Be Aware of Aggregators in the Search for Potential Human ecto-5 -Nucleotidase Inhibitors Reprinted from: Molecules 2018, 23, 1876, doi:10.3390/molecules23081876 .............. 78 Marian Vincenzi, Katarzyna Bednarska and Zbigniew J. Le´snikowski Comparative Study of Carborane- and Phenyl-Modified Adenosine Derivatives as Ligands for the A2A and A3 Adenosine Receptors Based on a Rigid in Silico Docking and Radioligand Replacement Assay Reprinted from: Molecules 2018, 23, 1846, doi:10.3390/molecules23081846 .............. 93 Eva-Maria Krammer, Jerome de Ruyck, Goedele Roos, Julie Bouckaert and Marc F. Lensink Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH Reprinted from: Molecules 2018, 23, 1641, doi:10.3390/molecules23071641 ..............114 v Mariarosaria Ferraro and Giorgio Colombo Targeting Difficult Protein-Protein Interactions with Plain and General Computational Approaches Reprinted from: Molecules 2018, 23, 2256, doi:10.3390/molecules23092256 ..............133 Tatu Pantsar and Antti Poso Binding Affinity via Docking: Fact and Fiction Reprinted from: Molecules 2018, 23, 1899, doi:10.3390/molecules23081899 ..............147 Wiktoria Jedwabny, Alessio Lodola and Edyta Dyguda-Kazimierowicz Theoretical Model of EphA2-Ephrin A1 Inhibition Reprinted from: Molecules 2018, 23, 1688, doi:10.3390/molecules23071688 ..............158 J´er´emie Mortier, Pratik Dhakal and Andrea Volkamer Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces Reprinted from: Molecules 2018, 23, 1959, doi:10.3390/molecules23081959 ..............177 Gerhard Hessler and Karl-Heinz Baringhaus Artificial Intelligence in Drug Design Reprinted from: Molecules 2018, 23, 2520, doi:10.3390/molecules23102520 ..............196 vi About the Special Issue Editors Rebecca C. Wade, Prof., Dr., is Professor of Computational Structural Biology at the Center for Molecular Biology at Heidelberg University (ZMBH) and leads the Molecular and Cellular Modeling group at Heidelberg Institute for Theoretical Studies (HITS). Rebecca C. Wade studied at Oxford University and received her doctorate in Molecular Biophysics in 1988. Following postdoctoral research at the universities of Houston and Illinois, she became a group leader at the European Molecular Biology Laboratory (EMBL) in Heidelberg in 1992. She moved to HITS in 2001. Her research is focused on the development and application of computer-aided methods to model and simulate biomolecular interactions. Ongoing research projects include Brownian dynamics simulations to investigate the macromolecular association and the effects of macromolecular crowding, molecular dynamics simulations to study how protein dynamics affect ligand binding mechanisms and kinetics, the development of methods to identify and analyze transient binding pockets in proteins, and the structure-based design of anti-parasitic agents against neglected diseases. Rebecca C. Wade’s research has resulted in over 200 scientific publications, as well as software programs and web servers that are used world-wide. She was the recipient of the 2004 Hansch Award of the QSAR and Modelling Society and the 2016 International Society of Quantum Biology and Pharmacology (ISQBP) Award in Computational Biology. Outi M. H. Salo-Ahen, Prof., PhD (Pharm.), gained her doctoral degree from the University of Eastern Finland in 2006. She was a postdoctoral Humboldt Fellow in Prof. Rebecca C. Wade’s group at the Heidelberg Institute of Theoretical Sciences (HITS), Germany 2006–2009. She returned to Finland to Prof. Mark Johnson’s Structural Bioinformatics Laboratory at the Abo˚ Akademi University, Turku and worked there as the Academy of Finland Postdoctoral Fellow 2011–2014. She is an acting Professor in Pharmacy at the Abo˚ Akademi University, Pharmaceutical Sciences Laboratory, Turku, Finland. Her research focuses on computer-aided drug design, especially anti-infective and anticancer agents. vii Preface to ”Molecular Modeling in Drug Design” Since the first attempts at structure-based drug design about four decades ago, molecular modelling techniques for drug design have developed enormously, along with the increasing computational power and structural and biological information on active compounds and potential target molecules. Nowadays, molecular modeling can be considered an integral component of the contemporary drug discovery and development process. Rational, target-based drug development projects benefit significantly from understanding the essential ligand–receptor interactions for designing a potent and efficacious drug that binds to the desired target or targets. Although current modeling techniques can provide important insight and speed up the drug discovery and design stages significantly, there are still many methodological challenges to overcome in the application of molecular modeling approaches to drug discovery. Some examples are the prediction of accurate ligand binding energies, the consideration of protein flexibility upon ligand binding, and the mapping of off-target effects of designed compounds. Moreover, there is also a need to develop methods for modelling bigger molecular entities, such as antibodies and nanoparticles, as well as targeting macromolecular interfaces. This book is based on the Special Issue of the journal Molecules on ‘Molecular Modeling in Drug Design’. This collection of research and review articles provides a snapshot of the state-of-the-art of molecular modeling in drug design, illustrating recent advances and critically discussing important challenges. The topics covered include virtual screening and pharmacophore modelling, chemoinformatic applications of artificial intelligence and machine learning, molecular dynamics simulation and enhanced sampling to investigate contributions of molecular flexibility to drug–receptor interactions, the modeling of drug–receptor solvation, hydrogen bonding and polarization, and drug design against protein–protein interfaces and membrane protein