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Allostery in Drug Discovery

Periodic Reporting for period 1 - ALLODD (Allostery in Drug Discovery)

Periodo di rendicontazione: 2021-09-01 al 2023-08-31

Most current drugs are designed to bind directly to the primary active sites (also known as orthosteric sites) of their biological targets. Drug discovery mainly focuses on modulation or inhibition ofprotein function through small molecules that bind to their primary active sites. However, protein function may also be regulated through drug binding to distant sites, known as allosteric sites. Allosteric modulators offer a powerful yet underexploited therapeutic approach. They can elicit a richer variety of biological responses and, since they target less conserved binding sites, higher selectivity and less adverse effects may be obtained. The EU-funded ALLODD project aims to overcome existing challenges in the discovery of allosteric modulators. Through state-of-the-art technologies, researchers aim to identify and characterise ligands capable of binding to allosteric sites of therapeutically relevant proteins, opening new possibilities in the drug discovery field.ALLODD aims to train a new generation of scientists in exploiting the concept of allostery in drug design, putting together a whole array of technologies to identify and characterize allosteric modulators of protein function that will be applied to therapeutically relevant systems.
Management

The Kick-Off meeting of the project was held on 24/9/2021. In order to ensure that the ALLODD project progresses in a consistent and homogeneous fashion during the first year of the project, the Coordinator organizes regular Board and Committee meetings according to the schedule described in the CA.
Due to important changes to the ALLODD Consortium and the project’s progress, an amendment to the GA was required. The Amendment was submitted to the Research Executive Agency, following a collective decision by the Consortium and it was accepted on March 22nd, 2022.

ESR Recruitment
13 of the 14 ALLODD ESRs were recruited between 1st November 2021 and 31st December 2022 according to the rules and procedures of the EC.

Research
The research part of ALLODD has been organized in five key objectives:
1. Identification of allosteric pockets
2. Identification of allosteric ligands
3. Understanding allostery at the molecular level
4. Understanding the biological response of allosteric ligands
5. Building a theoretical framework for allosteric modulation and a platform for the discovery of allosteric drugs

The first few months were dedicated in organising the ESR hiring process, to develop in greater detail the ESR projects and to set up the working infrastructures for the project.

Most ESRs are now in the second year of their PhD project and have been fully engaged in their research project. This is evidenced by the successful completion and submission of all deliverables (except D2.11 which was delayed due to the delayed recruitment of ESR9).

Training

The ALLODD consortium is acting at a multidisciplinary network level for achieving a collaborative training and research effort through a series of training schools for the ESRs as well as scientific consortium meetings, which enable the exchange of results and facilitate ESR training across ALLODD.

The first ALLODD Workshop & PhD Induction Course (04-06 April, 2022) was held in Vienna, Austria by UNIVIE. The workshop set the stage for the teaching the next generation of the ESRs in the framework of ALLODD. Starting with the introduction to the career development plan, the workshop set out to generate a better understanding for open science principles. While the ESRs received communications, research integrity and scientific writing training, the PIs had the opportunity to advance their knowledge on PhD supervision, leadership and coaching.

The second ALLODD meeting, the 1st Training School & Networking Meeting (13-17 June, 2022), was held in Barcelona, Spain and was hosted by UB. It started with a 2-day conference focusing on allosterism and drug discovery with several speakers from industry and academia. ESR presentations followed, in which each ESR shared information about their projects. The 4th day of the Event was dedicated to a negotiation training and inspirational talks about entrepreneurship.

The third ALLODD meeting, "Allostery in drug discovery awareness event and Symposium" and Workshop, was held at the University of Strasbourg 22-26 May 2023.

ALLODD is providing several training tools to the ESRs, to help them develop transferable skills and qualities, such as:
1. Blog posts
2. ALLODD Journal Club
3. ALLODD webinars
4. Meeting summaries
5. Lectures & Courses

Secondments
Secondments are a key component of the complementarity between ALLODD participants that is required to assimilate different research methodologies, ways of thinking and research cultures. ESRs are carrying out their secondments during their training period. During the secondments, the ESRs are acquiring the required skills for an optimum performance during their specific projects.

Career Development Plans
All ESRs have submitted a first version of their Career Development Plan. The purpose of the CDPs is to orientate the Supervisors and the Additional Supervisors to steer the ESRs to best prepare them for their career. The CDPs enable the development of research skills and techniques, independent research management, communication skills, networking and teamwork, career management and leadership skills. The CDPs are periodically individually updated after discussions of the ESRs and their mentors.

Outreach, Dissemination and Communication
The project website is set up (https://www.allodd-itn.eu) social media dissemination channels such as Twitter (https://twitter.com/ALLODD_ITN) and YouTube Channel (https://www.youtube.com/channel/UCPzJ2tTuJL8maIYWWkRTGwg) as well. ALLODD has been disseminated via conferences and satellite events as well as to the general public (e.g. “European Researchers' Night 2022”).

A list of publications by ALLODD can be found here: https://www.allodd-itn.eu/publications.html

The project is expected to deliver its maximum results after M36. Therefore, the exploitation strategy has not yet been adapted. However, the Coordinator took part in the Horizon Results BOOSTER workshop and the Consortium plans to request services, if applicable, after M36.
The ALLODD approach is based on a combination of experimental and simulation techniques, including fragment Screening with structural characterization (X-ray, NMR, H/D exchange), proteomics (MS/MS), ITC, DNA encoding libraries, Virtual Screening, Molecular Dynamics simulations-based methods, Synthetic Chemistry, and in vitro and cellular assays for the verification of results.

Allosteric targeting is expected to overcome existing challenges in the design of allosteric modulators. Through state-of-the-art technologies, researchers aim to identify and characterise ligands capable of binding to allosteric sites of therapeutically relevant proteins. Considerable effort will also go towards the generation of allosteric antibodies, opening new possibilities in the drug discovery field.

Allosteric targeting need not be achieved solely through the design of synthetic small molecules, but also can also be reached via conformationally specific allosteric antibodies, which represents an important field of future research. There are already clear examples of monoclonal antibodies that allosterically target ion channels, GPCRs and RTKs, as well as cytokine and integrin receptors.
ALLODD Events and Workshops
ALLODD Management and Governing Bodies Scheme
ALLODD Training Activities
ALLODD Consortium