Computational Pharmacy (Lill)Head of Research Unit Prof. Dr.Markus A. LillOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 5 foundShow per page10 10 20 50 Design of antimicrobial peptides through active learning Research Project | 2 Project MembersNo Description available Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism. Specificity, selectivity and pharmacokinetics of compstatin: a comprehensive multidisciplinary analysis Research Project | 6 Project MembersThe complement system plays a major role in innate immunity as it confers immune surveillance and first-line defense against non- or altered-self entities such as microbes or apoptotic cells. Yet, misguided complement activation may trigger or contribute to severe clinical conditions or complications, including autoimmune, hemolytic, inflammatory and age-related disorders and transplant rejection (PMID) [1]. Owing to its cascade organization, involving ~50 plasma proteins, receptors and enzymes, complement provides multiple points for novel pharmacological intervention [2]. However, few complement-targeted drugs have reached the clinic, and the available options primarily target peripheral steps in cascade initiation or effector generation. For many acute-phase or multifactorial complement disorders, blocking the activation of the central complement component C3 is considered important [3]. Derivatives of compstatin, a peptidic inhibitor of C3 activation [4], are the most advanced compounds in this class, with two candidate drugs being evaluated in clinical trials. However, its narrow species-specificity for primate C3 currently restricts a broader exploration of potential benefits of C3 inhibition in various established animal models of complement disorders. Furthermore, despite considerable progress in structure optimization, some pharmacokinetic and physicochemical properties of the compstatin class remain to be improved to fully unleash its unique therapeutic potential. The main objective of this project is to understand target binding and complement inhibition by compstatin in the human system at the atomic level and identify key determinants of its narrow species specificity. We will utilize this knowledge for designing compstatin analogs that recognize non-primate C3 and, for example, inhibit mouse, rat or pig complement. Simultaneously, we will assess compstatin's target selectivity for C3 over the orthologous C4 and C5 proteins and explore options for achieving C4-, C5- or pan-specific inhibitors for research or clinical applications. Finally, we will analyze and optimize the pharmacokinetic properties of compstatin with special emphasis on solubility and bioavailability. The proposed rationalization and optimization efforts will be driven by well-established in silico simulation techniques such as molecular dynamics simulations, free energy methods, homology modeling, and post-MD analyses, supported by novel approaches based on deep learning (Prof. Markus Lill, Computational Pharmacy). Thanks to project collaborations with strong experimental groups, in silico findings will be experimentally verified by employing peptide synthesis and characterization, chemical modification and labeling, and target binding and functional assays in vitro (Prof. Daniel Ricklin, Molecular Pharmacy) as well as pre-clinical assessments of cellular permeability in vitro and in vivo (Prof. Henriette Meyer zu Schwabedissen, Biopharmacy; all at University of Basel). Our studies are expected to extend preclinical evaluation options of compstatin-based drugs in animal models and enhance their pharmacokinetic profile, thereby facilitating clinical development of this important inhibitor class. Selectivity studies with C4/C5 may provide insight into complement activation and potentially reveal novel inhibitors. Finally, atomic level insight into the structure-activity/property relationships of cyclic peptides may be used for the design of this compound type in general. [1] Ricklin, D.; Reis, E. S.; Lambris, J. D. Complement in Disease: A Defence System Turning Offensive. Nat. Rev. Nephrol. 2016, 12 (7), 383-401. https://doi.org/10.1038/nrneph.2016.70. [2] Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707-729 (2019). https://doi.org/10.1038/s41573-019-0031-6 [3] Mastellos, D. C.; Reis, E. S.; Ricklin, D.; Smith, R. J.; Lambris, J. D. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol. 2017, 38 (6), 383-394. https://doi.org/10.1016/j.it.2017.03.003. [4] Mastellos, D. C.; Yancopoulou, D.; Kokkinos, P.; Huber-Lang, M.; Hajishengallis, G.; Biglarnia, A. R.; Lupu, F.; Nilsson, B.; Risitano, A. M.; Ricklin, D.; Lambris, J. D. Compstatin: A C3-Targeted Complement Inhibitor Reaching Its Prime for Bedside Intervention. Eur. J. Clin. Invest. 2015, 45 (4), 423-440. https://doi.org/10.1111/eci.12419. Development of in silico screening tools and in vitro bioassays for 5α- and 5β-reductase Research Project | 3 Project MembersThe proposed project focuses on two important enzymes involved in the hepatic metabolism/degradation of steroid hormones in the human body: 5α-reductase (SRD5A1) and 5β-reductase (AKR1D1). More exactly, both enzymes are very important in maintaining the androgen-glucocorticoid balance. Thus, any undesired interaction (inhibition) by small molecules (e.g. drugs, cosmetics, food additives, natural compounds) would result in altered activity of the enzymes and potentially lead to disruption of the steroid homeostasis. Increased levels of glucocorticoids may severely affect human health in terms of increased risk for development of metabolic diseases, including diabetes and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatosis (NASH) [1-3]. The main goal of this project proposal is to develop in silico predictive models for screening of small molecules in order to rapidly and reliably identify their undesired interaction with the two enzymes. The project requests one year funding for a PhD student who will get training and subsequently apply various state-of-the-art modeling techniques like molecular docking, pose scoring, homology modeling, molecular dynamics simulations to elucidate enzyme-ligand interactions at the atomic level in silico as well as establish experimental activity assays for initial testing and validation of screening hits. The modelling information together with the enzyme activity data will allow defining structure-activity-relationships for the two enzymes. 1. Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, Hughes B, Taylor A, Bujalska IJ, Gathercole LL, Tomlinson JW: 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes. Endocrinology. 2015, 156(8):2863-71. doi: 10.1210/en.2015-1149. 2. Dowman JK, Hopkins LJ, Reynolds GM, Armstrong MJ, Nasiri M, Nikolaou N, van Houten EL, Visser JA, Morgan SA, Lavery GG, Oprescu A, Hübscher SG, Newsome PN, Tomlinson JW.: Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice. Endocrinology. 2013, 154(12):4536-47. doi: 10.1210/en.2013-1592. 3. Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Macfarlane DP, Marshall I, Stewart LH, Walker BR, Andrew R.: 5α-reductase type 1 modulates insulin sensitivity in men. J. Clin. Endocrinol. Metab. 2014, 99(8):E1397-406. doi: 10.1210/jc.2014-1395. Entwicklung einer in silico Plattform zur Früherkennung von Nebenwirkungen Research Project | 2 Project MembersModern society needs new chemical compounds like pharmaceuticals, cosmetics, agrochemicals, food additives, as well as natural compounds to maintain and further improve the standard of living. According to regulations, all chemicals that may come to contact with humans have to be fully characterised, including information about their possible harmful effects. Such a detailed characterisation is not only resource intensive, but also results in extensive animal testing. Fortunately, in silico methods offer a cost-effective and ethical alternative. Ever increasing computational power in combination with the latest knowledge from multiple disciplines allow us to perform virtual experiments by means of computer simulation. Thus, we can learn about the nature of the chemical compound without need to have it physically synthesized and tested on animals. This means, that the extent of animal testing can be effectively reduced - it is performed only using the safest, computationally pre-evaluated compounds. Increased expected safety translates to animal testing reduced to inevitable minimum required for the regulatory approval. The goal of this grant proposal is to develop and maintain a modular in silico screening platform which could be used to effectively identify possible harmful interference of chemicals with human proteins termed "anti-targets", as any interaction with them is undesired. Using the most advanced simulations and modeling methods we would actively search for so-called molecular initiating events. These events are the first step in a complex cascade of processes eventually leading to an adverse outcome. With this approach, we present a cost and resource effective alternative to conventional chemical risk assessment. 1 1 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 5 foundShow per page10 10 20 50 Design of antimicrobial peptides through active learning Research Project | 2 Project MembersNo Description available Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism. Specificity, selectivity and pharmacokinetics of compstatin: a comprehensive multidisciplinary analysis Research Project | 6 Project MembersThe complement system plays a major role in innate immunity as it confers immune surveillance and first-line defense against non- or altered-self entities such as microbes or apoptotic cells. Yet, misguided complement activation may trigger or contribute to severe clinical conditions or complications, including autoimmune, hemolytic, inflammatory and age-related disorders and transplant rejection (PMID) [1]. Owing to its cascade organization, involving ~50 plasma proteins, receptors and enzymes, complement provides multiple points for novel pharmacological intervention [2]. However, few complement-targeted drugs have reached the clinic, and the available options primarily target peripheral steps in cascade initiation or effector generation. For many acute-phase or multifactorial complement disorders, blocking the activation of the central complement component C3 is considered important [3]. Derivatives of compstatin, a peptidic inhibitor of C3 activation [4], are the most advanced compounds in this class, with two candidate drugs being evaluated in clinical trials. However, its narrow species-specificity for primate C3 currently restricts a broader exploration of potential benefits of C3 inhibition in various established animal models of complement disorders. Furthermore, despite considerable progress in structure optimization, some pharmacokinetic and physicochemical properties of the compstatin class remain to be improved to fully unleash its unique therapeutic potential. The main objective of this project is to understand target binding and complement inhibition by compstatin in the human system at the atomic level and identify key determinants of its narrow species specificity. We will utilize this knowledge for designing compstatin analogs that recognize non-primate C3 and, for example, inhibit mouse, rat or pig complement. Simultaneously, we will assess compstatin's target selectivity for C3 over the orthologous C4 and C5 proteins and explore options for achieving C4-, C5- or pan-specific inhibitors for research or clinical applications. Finally, we will analyze and optimize the pharmacokinetic properties of compstatin with special emphasis on solubility and bioavailability. The proposed rationalization and optimization efforts will be driven by well-established in silico simulation techniques such as molecular dynamics simulations, free energy methods, homology modeling, and post-MD analyses, supported by novel approaches based on deep learning (Prof. Markus Lill, Computational Pharmacy). Thanks to project collaborations with strong experimental groups, in silico findings will be experimentally verified by employing peptide synthesis and characterization, chemical modification and labeling, and target binding and functional assays in vitro (Prof. Daniel Ricklin, Molecular Pharmacy) as well as pre-clinical assessments of cellular permeability in vitro and in vivo (Prof. Henriette Meyer zu Schwabedissen, Biopharmacy; all at University of Basel). Our studies are expected to extend preclinical evaluation options of compstatin-based drugs in animal models and enhance their pharmacokinetic profile, thereby facilitating clinical development of this important inhibitor class. Selectivity studies with C4/C5 may provide insight into complement activation and potentially reveal novel inhibitors. Finally, atomic level insight into the structure-activity/property relationships of cyclic peptides may be used for the design of this compound type in general. [1] Ricklin, D.; Reis, E. S.; Lambris, J. D. Complement in Disease: A Defence System Turning Offensive. Nat. Rev. Nephrol. 2016, 12 (7), 383-401. https://doi.org/10.1038/nrneph.2016.70. [2] Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707-729 (2019). https://doi.org/10.1038/s41573-019-0031-6 [3] Mastellos, D. C.; Reis, E. S.; Ricklin, D.; Smith, R. J.; Lambris, J. D. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol. 2017, 38 (6), 383-394. https://doi.org/10.1016/j.it.2017.03.003. [4] Mastellos, D. C.; Yancopoulou, D.; Kokkinos, P.; Huber-Lang, M.; Hajishengallis, G.; Biglarnia, A. R.; Lupu, F.; Nilsson, B.; Risitano, A. M.; Ricklin, D.; Lambris, J. D. Compstatin: A C3-Targeted Complement Inhibitor Reaching Its Prime for Bedside Intervention. Eur. J. Clin. Invest. 2015, 45 (4), 423-440. https://doi.org/10.1111/eci.12419. Development of in silico screening tools and in vitro bioassays for 5α- and 5β-reductase Research Project | 3 Project MembersThe proposed project focuses on two important enzymes involved in the hepatic metabolism/degradation of steroid hormones in the human body: 5α-reductase (SRD5A1) and 5β-reductase (AKR1D1). More exactly, both enzymes are very important in maintaining the androgen-glucocorticoid balance. Thus, any undesired interaction (inhibition) by small molecules (e.g. drugs, cosmetics, food additives, natural compounds) would result in altered activity of the enzymes and potentially lead to disruption of the steroid homeostasis. Increased levels of glucocorticoids may severely affect human health in terms of increased risk for development of metabolic diseases, including diabetes and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatosis (NASH) [1-3]. The main goal of this project proposal is to develop in silico predictive models for screening of small molecules in order to rapidly and reliably identify their undesired interaction with the two enzymes. The project requests one year funding for a PhD student who will get training and subsequently apply various state-of-the-art modeling techniques like molecular docking, pose scoring, homology modeling, molecular dynamics simulations to elucidate enzyme-ligand interactions at the atomic level in silico as well as establish experimental activity assays for initial testing and validation of screening hits. The modelling information together with the enzyme activity data will allow defining structure-activity-relationships for the two enzymes. 1. Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, Hughes B, Taylor A, Bujalska IJ, Gathercole LL, Tomlinson JW: 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes. Endocrinology. 2015, 156(8):2863-71. doi: 10.1210/en.2015-1149. 2. Dowman JK, Hopkins LJ, Reynolds GM, Armstrong MJ, Nasiri M, Nikolaou N, van Houten EL, Visser JA, Morgan SA, Lavery GG, Oprescu A, Hübscher SG, Newsome PN, Tomlinson JW.: Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice. Endocrinology. 2013, 154(12):4536-47. doi: 10.1210/en.2013-1592. 3. Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Macfarlane DP, Marshall I, Stewart LH, Walker BR, Andrew R.: 5α-reductase type 1 modulates insulin sensitivity in men. J. Clin. Endocrinol. Metab. 2014, 99(8):E1397-406. doi: 10.1210/jc.2014-1395. Entwicklung einer in silico Plattform zur Früherkennung von Nebenwirkungen Research Project | 2 Project MembersModern society needs new chemical compounds like pharmaceuticals, cosmetics, agrochemicals, food additives, as well as natural compounds to maintain and further improve the standard of living. According to regulations, all chemicals that may come to contact with humans have to be fully characterised, including information about their possible harmful effects. Such a detailed characterisation is not only resource intensive, but also results in extensive animal testing. Fortunately, in silico methods offer a cost-effective and ethical alternative. Ever increasing computational power in combination with the latest knowledge from multiple disciplines allow us to perform virtual experiments by means of computer simulation. Thus, we can learn about the nature of the chemical compound without need to have it physically synthesized and tested on animals. This means, that the extent of animal testing can be effectively reduced - it is performed only using the safest, computationally pre-evaluated compounds. Increased expected safety translates to animal testing reduced to inevitable minimum required for the regulatory approval. The goal of this grant proposal is to develop and maintain a modular in silico screening platform which could be used to effectively identify possible harmful interference of chemicals with human proteins termed "anti-targets", as any interaction with them is undesired. Using the most advanced simulations and modeling methods we would actively search for so-called molecular initiating events. These events are the first step in a complex cascade of processes eventually leading to an adverse outcome. With this approach, we present a cost and resource effective alternative to conventional chemical risk assessment. 1 1
Design of antimicrobial peptides through active learning Research Project | 2 Project MembersNo Description available
Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism.
Specificity, selectivity and pharmacokinetics of compstatin: a comprehensive multidisciplinary analysis Research Project | 6 Project MembersThe complement system plays a major role in innate immunity as it confers immune surveillance and first-line defense against non- or altered-self entities such as microbes or apoptotic cells. Yet, misguided complement activation may trigger or contribute to severe clinical conditions or complications, including autoimmune, hemolytic, inflammatory and age-related disorders and transplant rejection (PMID) [1]. Owing to its cascade organization, involving ~50 plasma proteins, receptors and enzymes, complement provides multiple points for novel pharmacological intervention [2]. However, few complement-targeted drugs have reached the clinic, and the available options primarily target peripheral steps in cascade initiation or effector generation. For many acute-phase or multifactorial complement disorders, blocking the activation of the central complement component C3 is considered important [3]. Derivatives of compstatin, a peptidic inhibitor of C3 activation [4], are the most advanced compounds in this class, with two candidate drugs being evaluated in clinical trials. However, its narrow species-specificity for primate C3 currently restricts a broader exploration of potential benefits of C3 inhibition in various established animal models of complement disorders. Furthermore, despite considerable progress in structure optimization, some pharmacokinetic and physicochemical properties of the compstatin class remain to be improved to fully unleash its unique therapeutic potential. The main objective of this project is to understand target binding and complement inhibition by compstatin in the human system at the atomic level and identify key determinants of its narrow species specificity. We will utilize this knowledge for designing compstatin analogs that recognize non-primate C3 and, for example, inhibit mouse, rat or pig complement. Simultaneously, we will assess compstatin's target selectivity for C3 over the orthologous C4 and C5 proteins and explore options for achieving C4-, C5- or pan-specific inhibitors for research or clinical applications. Finally, we will analyze and optimize the pharmacokinetic properties of compstatin with special emphasis on solubility and bioavailability. The proposed rationalization and optimization efforts will be driven by well-established in silico simulation techniques such as molecular dynamics simulations, free energy methods, homology modeling, and post-MD analyses, supported by novel approaches based on deep learning (Prof. Markus Lill, Computational Pharmacy). Thanks to project collaborations with strong experimental groups, in silico findings will be experimentally verified by employing peptide synthesis and characterization, chemical modification and labeling, and target binding and functional assays in vitro (Prof. Daniel Ricklin, Molecular Pharmacy) as well as pre-clinical assessments of cellular permeability in vitro and in vivo (Prof. Henriette Meyer zu Schwabedissen, Biopharmacy; all at University of Basel). Our studies are expected to extend preclinical evaluation options of compstatin-based drugs in animal models and enhance their pharmacokinetic profile, thereby facilitating clinical development of this important inhibitor class. Selectivity studies with C4/C5 may provide insight into complement activation and potentially reveal novel inhibitors. Finally, atomic level insight into the structure-activity/property relationships of cyclic peptides may be used for the design of this compound type in general. [1] Ricklin, D.; Reis, E. S.; Lambris, J. D. Complement in Disease: A Defence System Turning Offensive. Nat. Rev. Nephrol. 2016, 12 (7), 383-401. https://doi.org/10.1038/nrneph.2016.70. [2] Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707-729 (2019). https://doi.org/10.1038/s41573-019-0031-6 [3] Mastellos, D. C.; Reis, E. S.; Ricklin, D.; Smith, R. J.; Lambris, J. D. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol. 2017, 38 (6), 383-394. https://doi.org/10.1016/j.it.2017.03.003. [4] Mastellos, D. C.; Yancopoulou, D.; Kokkinos, P.; Huber-Lang, M.; Hajishengallis, G.; Biglarnia, A. R.; Lupu, F.; Nilsson, B.; Risitano, A. M.; Ricklin, D.; Lambris, J. D. Compstatin: A C3-Targeted Complement Inhibitor Reaching Its Prime for Bedside Intervention. Eur. J. Clin. Invest. 2015, 45 (4), 423-440. https://doi.org/10.1111/eci.12419.
Development of in silico screening tools and in vitro bioassays for 5α- and 5β-reductase Research Project | 3 Project MembersThe proposed project focuses on two important enzymes involved in the hepatic metabolism/degradation of steroid hormones in the human body: 5α-reductase (SRD5A1) and 5β-reductase (AKR1D1). More exactly, both enzymes are very important in maintaining the androgen-glucocorticoid balance. Thus, any undesired interaction (inhibition) by small molecules (e.g. drugs, cosmetics, food additives, natural compounds) would result in altered activity of the enzymes and potentially lead to disruption of the steroid homeostasis. Increased levels of glucocorticoids may severely affect human health in terms of increased risk for development of metabolic diseases, including diabetes and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatosis (NASH) [1-3]. The main goal of this project proposal is to develop in silico predictive models for screening of small molecules in order to rapidly and reliably identify their undesired interaction with the two enzymes. The project requests one year funding for a PhD student who will get training and subsequently apply various state-of-the-art modeling techniques like molecular docking, pose scoring, homology modeling, molecular dynamics simulations to elucidate enzyme-ligand interactions at the atomic level in silico as well as establish experimental activity assays for initial testing and validation of screening hits. The modelling information together with the enzyme activity data will allow defining structure-activity-relationships for the two enzymes. 1. Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, Hughes B, Taylor A, Bujalska IJ, Gathercole LL, Tomlinson JW: 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes. Endocrinology. 2015, 156(8):2863-71. doi: 10.1210/en.2015-1149. 2. Dowman JK, Hopkins LJ, Reynolds GM, Armstrong MJ, Nasiri M, Nikolaou N, van Houten EL, Visser JA, Morgan SA, Lavery GG, Oprescu A, Hübscher SG, Newsome PN, Tomlinson JW.: Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice. Endocrinology. 2013, 154(12):4536-47. doi: 10.1210/en.2013-1592. 3. Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Macfarlane DP, Marshall I, Stewart LH, Walker BR, Andrew R.: 5α-reductase type 1 modulates insulin sensitivity in men. J. Clin. Endocrinol. Metab. 2014, 99(8):E1397-406. doi: 10.1210/jc.2014-1395.
Entwicklung einer in silico Plattform zur Früherkennung von Nebenwirkungen Research Project | 2 Project MembersModern society needs new chemical compounds like pharmaceuticals, cosmetics, agrochemicals, food additives, as well as natural compounds to maintain and further improve the standard of living. According to regulations, all chemicals that may come to contact with humans have to be fully characterised, including information about their possible harmful effects. Such a detailed characterisation is not only resource intensive, but also results in extensive animal testing. Fortunately, in silico methods offer a cost-effective and ethical alternative. Ever increasing computational power in combination with the latest knowledge from multiple disciplines allow us to perform virtual experiments by means of computer simulation. Thus, we can learn about the nature of the chemical compound without need to have it physically synthesized and tested on animals. This means, that the extent of animal testing can be effectively reduced - it is performed only using the safest, computationally pre-evaluated compounds. Increased expected safety translates to animal testing reduced to inevitable minimum required for the regulatory approval. The goal of this grant proposal is to develop and maintain a modular in silico screening platform which could be used to effectively identify possible harmful interference of chemicals with human proteins termed "anti-targets", as any interaction with them is undesired. Using the most advanced simulations and modeling methods we would actively search for so-called molecular initiating events. These events are the first step in a complex cascade of processes eventually leading to an adverse outcome. With this approach, we present a cost and resource effective alternative to conventional chemical risk assessment.
