Periodic Reporting for period 1 - DREAMY (Disrupting Aberrant Protein–Protein Interactions with Conformationally Constrained Hydrocarbon α-Helical Mimetics)
Período documentado: 2018-10-10 hasta 2020-10-09
Overall assessment: The project has achieved most of its objectives and milestones for the period, with relatively minor deviations.
It is well known that the conformation of a molecule is often critical to its desired function. This is especially true for drug molecules that typically need to access a particular conformation in order to preferentially interact with its receptor. The pharmaceutical industry has stereotypically focused its attention on small, heterocyclic rigid molecules that do not have complicated conformational landscapes. However, in recent years more complex receptors, with large binding domains, have come to the attention of pharmaceutical scientists and the traditional small rigid molecules are inadequate at targeting such large receptors. Therefore, there has been increased interest in the design, synthesis, and analysis of conformationally constrained molecules to target large binding sites. A classic example is the design of α-helix mimetics that can target aberrant protein-protein interactions.
Controlling molecular conformation is not limited to the introduction of intramolecular interactions within a molecule. Introducing destabilizing interactions, such as the syn-pentane interaction, has also been shown to be effective at controlling molecular conformation. The host laboratory has successfully introduced destabilizing interactions such as the syn-pentane interactions and created an organic molecule with tailored shapes. According to the host group, substituted carbon chains can be grown one carbon atom at a time with exquisite control of relative and absolute configuration through iterative homologation of boronic esters with stereochemically-defined lithiated carbamates or benzoates. When a boronic ester is treated with a lithiated carbamate or benzoate, a boronate complex is formed which upon warming undergoes 1,2-migration—the organic group on boron migrates to the neighboring carbon atom with the expulsion of the carbamate or benzoate—giving a new boronic ester, a one-carbon-extended version of the starting boronic ester. This process can be repeated with the newly formed boronic ester, either by using the same or the opposite enantiomer of the lithiated benzoate/carbamate or indeed a differently substituted benzoate/carbamate. It was also realized that depending on the relationship between the methyl groups of a fully methylated hydrocarbon, specific conformations of the backbone would be adopted to avoid destabilizing syn-pentane interactions. All-syn contiguously methyl-substituted hydrocarbons will adopt alternating g+/- t (±60°, 180°) dihedral angles, resulting in a helical conformation whilst alternating syn-anti substitution patterns will adopt t dihedral angles, resulting in a linear conformation. It was recognized that for both the linear and helical structures the distance between the side chains that are on the same face of the linear or helical backbone closely resembles the distance between residues on one face of an α-helix. For the linear structure, distances of ~5.3 Å are observed and for the helical structure distances of ~6.5 Å are observed. Comparing this to the distances between residues in an α-helix (5-7 Å), we propose that the linear and helical scaffolds would make suitable α-helical mimetics (Picture1).
It is well known that the conformation of a molecule is often critical to its desired function. This is especially true for drug molecules that typically need to access a particular conformation in order to preferentially interact with its receptor. The pharmaceutical industry has stereotypically focused its attention on small, heterocyclic rigid molecules that do not have complicated conformational landscapes. However, in recent years more complex receptors, with large binding domains, have come to the attention of pharmaceutical scientists and the traditional small rigid molecules are inadequate at targeting such large receptors. Therefore, there has been increased interest in the design, synthesis, and analysis of conformationally constrained molecules to target large binding sites. A classic example is the design of α-helix mimetics that can target aberrant protein-protein interactions.
Controlling molecular conformation is not limited to the introduction of intramolecular interactions within a molecule. Introducing destabilizing interactions, such as the syn-pentane interaction, has also been shown to be effective at controlling molecular conformation. The host laboratory has successfully introduced destabilizing interactions such as the syn-pentane interactions and created an organic molecule with tailored shapes. According to the host group, substituted carbon chains can be grown one carbon atom at a time with exquisite control of relative and absolute configuration through iterative homologation of boronic esters with stereochemically-defined lithiated carbamates or benzoates. When a boronic ester is treated with a lithiated carbamate or benzoate, a boronate complex is formed which upon warming undergoes 1,2-migration—the organic group on boron migrates to the neighboring carbon atom with the expulsion of the carbamate or benzoate—giving a new boronic ester, a one-carbon-extended version of the starting boronic ester. This process can be repeated with the newly formed boronic ester, either by using the same or the opposite enantiomer of the lithiated benzoate/carbamate or indeed a differently substituted benzoate/carbamate. It was also realized that depending on the relationship between the methyl groups of a fully methylated hydrocarbon, specific conformations of the backbone would be adopted to avoid destabilizing syn-pentane interactions. All-syn contiguously methyl-substituted hydrocarbons will adopt alternating g+/- t (±60°, 180°) dihedral angles, resulting in a helical conformation whilst alternating syn-anti substitution patterns will adopt t dihedral angles, resulting in a linear conformation. It was recognized that for both the linear and helical structures the distance between the side chains that are on the same face of the linear or helical backbone closely resembles the distance between residues on one face of an α-helix. For the linear structure, distances of ~5.3 Å are observed and for the helical structure distances of ~6.5 Å are observed. Comparing this to the distances between residues in an α-helix (5-7 Å), we propose that the linear and helical scaffolds would make suitable α-helical mimetics (Picture1).
The project has mostly achieved its objectives and milestones proposed in the original DoA and some minor modifications of the original plan were found to be necessary. The following project milestones were achieved: 1. Understanding and controlling molecular conformation. 2. The computational design of a suitable scaffold. 3. The Synthesis of an α-Helix Mimetic of Noxa-B. 4. The Analysis of Molecular Conformation using a hybrid NMR Spectroscopy and Molecular Mechanical/Quantum Mechanical Computational Approach. 5. Analyse the binding of the ligands to Mcl-1. Overall, this work marks one of the strongest examples of conformational control being imposed into a flexible molecule through the introduction of substituents along the hydrocarbon chain that controls the conformation through the avoidance of destabilizing syn-pentane interactions. We are confident that this work has demonstrated how conformationally controlled hydrocarbons are displaying promise in the design of inhibitors of the aberrant protein-protein interactions.
Most of the tasks detailed in the DoA have been successfully achieved, except for minor modifications. The plan for dissemination has also been followed with just minor modifications. The description of the impact detailed in the original DoA is, therefore, still relevant for this project.
Overall, the general impact could be described as following.
Impact on the researcher's career. The Fellow has gained a lot of training and experiences during the implementation of this project. He has also established his research network with many outstanding young chemists in the host group and has established good collaborations in the field of boron and PPI chemistry. As a result, the fellow has been invited for in-person and skype interviews for his individual academic position in the highly reputed universities in India. The Fellow has recently received a job opportunity in CSIR-INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY-HYD as senior project scientist-II which is one step ahead of his ultimate academic goal, to become a research faculty in the reputed university in India.
Contributing to European Research Area and EU priorities. Harnessing chemical technologies effectively and sustainably is a key element for achieving EU sustainable development. This project introduces an efficient methodology for the PPI inhibitors. This will contribute to ensuring an EU sustainable future.
Impact on the academic community. The chemistry detailed in this action has tremendously impacted academia, triggering growing interest in the topics discovered.
Impact on the industry. It has been noticed that the efficiency of drug development has been decreasing in the past few decades. To overcome the situation, protein-protein interactions (PPIs) have been identified as new drug targets as early as 2000. Indeed, protein-protein interactions have attracted the attention of pharmaceutical industries and academic scientists who are interested in developing new therapeutic agents. In this regard, we demonstrated how conformationally controlled hydrocarbons are displaying promise in the design of inhibitors of the aberrant protein-protein interactions. The chemistry discovered during this project opened new significant chemical space in the field of PPI inhibitors.
Overall, the general impact could be described as following.
Impact on the researcher's career. The Fellow has gained a lot of training and experiences during the implementation of this project. He has also established his research network with many outstanding young chemists in the host group and has established good collaborations in the field of boron and PPI chemistry. As a result, the fellow has been invited for in-person and skype interviews for his individual academic position in the highly reputed universities in India. The Fellow has recently received a job opportunity in CSIR-INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY-HYD as senior project scientist-II which is one step ahead of his ultimate academic goal, to become a research faculty in the reputed university in India.
Contributing to European Research Area and EU priorities. Harnessing chemical technologies effectively and sustainably is a key element for achieving EU sustainable development. This project introduces an efficient methodology for the PPI inhibitors. This will contribute to ensuring an EU sustainable future.
Impact on the academic community. The chemistry detailed in this action has tremendously impacted academia, triggering growing interest in the topics discovered.
Impact on the industry. It has been noticed that the efficiency of drug development has been decreasing in the past few decades. To overcome the situation, protein-protein interactions (PPIs) have been identified as new drug targets as early as 2000. Indeed, protein-protein interactions have attracted the attention of pharmaceutical industries and academic scientists who are interested in developing new therapeutic agents. In this regard, we demonstrated how conformationally controlled hydrocarbons are displaying promise in the design of inhibitors of the aberrant protein-protein interactions. The chemistry discovered during this project opened new significant chemical space in the field of PPI inhibitors.