Computer-Aided Drug Design in the EuroNeurotrophin Project
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Neurotrophins are protein growth factors that are present in the central and peripheral nervous system. Neurotrophins and their receptors play a key role in the proper function of the nervous system, as they modulate several signaling pathways that regulate neuronal survival, axonal and dendritic network maintenance, as well as synaptic plasticity (Gomez et al. 2013). Neurotrophins could serve as a treatment in a number of neurological disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis (Allen et Dawbarn, 2006), (Chao et al. 2006). However, their suboptimal pharmacological properties have hindered them from being used as therapeutics against neurodegenerative diseases. A solution to this problem is the development of small molecule neurotrophin mimetics that specifically target the neurotrophin receptors. This approach is pursued in the EuroNeurotrophin consortium by concerted efforts in computer-aided drug design, medicinal chemistry, structural and molecular biology. The contributions of in silico methodologies to the quest for neurotrophin mimetics will be described.
Computer-aided drug design has successfully contributed to the discovery of agents against brain diseases. For example, compounds that inhibit and reverse amyloid-β aggregation and neurotoxicity, as well as inhibitors against β-secretase (BACE-1) have been identified as lead molecules for the treatment of Alzheimer's disease by pharmacophore modeling, database screening and molecular docking methods (Zeng and Wu, 2016). In the EuroNeurotrophin consortium, computational work is performed for the discovery of neurotrophin mimetics. The PhD students working on the computational aspects of the project evaluate lead-molecule optimization efforts by medicinal chemists in the consortium and identify new chemical scaffolds with neurotrophin mimetic activity by virtual screening of compound libraries and isolated marine products provided by other partners in the consortium. They also predict or calculate the Absorption, Distribution, Metabolism, Excretion (ADME) properties of various small molecules tested within the project in order to identify potentially undesired properties of a compound that should be addressed in the compound design phase. Molecular dynamics simulations of the neurotrophin receptors and the compounds are employed to study the dynamical behavior of these systems. All of these calculations enable the prioritization of the most promising compounds, thus establishing a compound design process that is more efficient than serendipitous drug discovery efforts. Some of the results of this work have been presented at the EFMC-ASMC'19 8th EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry, the EFMC-YSMC’19 6th EFMC Young Medicinal Chemist Symposium, and the 65th Biophysical Society Annual Meeting 2021. In addition to research in computer-aided drug design, the EuroNeurotrophin members at Heidelberg Institute for Theoretical Studies (HITS) provided the PhD students in the consortium with training in computational techniques, an aspect that is important for both the well-rounded doctoral training of the students, and for the efficient collaboration between the computational and experimental groups in the consortium. Specifically, a workshop on computer-assisted drug design was held during the 1st EuroNeurotrophin Training Week in Athens, Greece in 2018, in the context of which the participants received training on molecular docking and molecular dynamics simulation techniques. Furthermore, a workshop on bioinformatic analysis of protein structures and the prediction of protein binding properties was held during the online 3rd EuroNeurotrophin Training Week in 2020. Finally, HITS has been a host institute for secondments of three other PhD students from the consortium, who had the opportunity to become familiar with in silico methodologies and do computational research related to their PhD project. 
Crystal structure of a neurotrophin (in red) bound to its receptor (in gray), showing the amino acid residues in the interface that participate in interactions between the two proteins. Mimetic compounds can be designed to form similar interactions with the neurotrophin receptors or to enhance the effects of neurotrophins, e.g. by stabilizing neurotrophin-receptor com-plexes. Original structure PDB ID 1WWW (Wiesmann, C., Ultsch, M., Bass, S. et al. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401, 184–188 (1999). https://doi.org/10.1038/43705).
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Alexandros is hosted at the HITS gGmbH, Heidelberg Institute for Theoretical Studies and he works on the design and optimization of small molecule mimetics and potentiators of neurotrophins, using a combination of in silico ligand-based and receptor-based drug design approaches
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