Within every human cell, nature has engineered finely-tuned control mechanisms to correct imbalances caused by stress and disease and promote healing. At Hotspot Therapeutics, nature is inspiring us to create a wave of new medicines.
Through a proprietary technology platform, we are uncovering privileged allosteric sites used by nature to control proteins – called regulatory hotspots– that can be exploited through small molecule drug discovery. Regulatory hotspots are allowing sought-after targets to be drugged for the first time while delivering molecules with exquisite selectivity, unshifted in vivo potency and attractive drug-like properties.
HotSpot is supported by a syndicate of leading healthcare investors based in the US and Europe.
You are a highly motivated, creative and collaborative computational chemist. You want to play a critical role in optimizing small molecules towards clinical candidates that have the potential to dramatically improve the lives of patients with serious diseases. You are excited about applying a broad set of computational tools including both structure- and ligand-based approaches to achieve a deep understanding of structure-activity relationships (SAR). You are looking to shape structural and druggability components of HotSpot’s target identification platform (SpotFinderTM) to uncover regulatory hotspots across the proteome. You have a passion for how structure informs biological function. You are eager to recommend targets to be pursued for drug discovery based on the output from the platform.
You will be joining a seasoned team of drug hunters with an excellent track record in drug discovery. As a HotSpotter, you are comfortable thinking outside the box and breaking convention. You are curious about the world and contribute beyond your precise role description. You can think strategically in one moment, but then roll your sleeves up to troubleshoot an experimental protocol in the next. You are action orientated and extraordinary at getting things done. You communicate openly with your colleagues and you hate office politics.
You will be responsible for structure-based drug design and the development of the technology platform. As part of a multi-disciplinary team, you will contribute to new target selection and will serve as the computational lead on multiple drug discovery programs as they progress from initial virtual screening through to candidate nomination. You will be developing the strategy for the structure and ligand components of SpotFinderTM and managing their execution through internal and external teams.
Your responsibilities will include the following:
Lead structure-based drug design activities for priority programs
- Develop deep understanding of project SAR, and in concert apply cutting edge computational chemistry methods to influence team strategy and compound design, and ultimately positively impact project direction
- Apply predictive technologies (in silico, protein structure-based & profiling) beyond SAR into predictive ADME, safety/toxicity and attrition
- Drive development of in silico screening libraries including those biased towards hotspots. Identify sources of commercially available chemical matter
- Manage external and internal modeling teams (3+ FTEs); it is desirable to manage chemical-biological data system, and computing resources available at Amazon’s AWS
Drive development of the integrated software platform for identifying validated, druggable hotspots
- Develop strategies for identification of hotspots with specific structure-function characteristics e.g. cis-regulatory tails
- Leverage broad set of tools including structure/ligand-based and bioinformatics approaches, artificial intelligence (AI), machine learning
- Manage all aspects of computational chemistry work up supporting target nomination
- Drive development of databases that capture key features of most attractive regulatory hotspots
- Scout external sources for applicable technologies and collaborations; evaluate/pilot as appropriate
- Drive development of display methods that clearly communicate platform output
- Develop approaches to enhance platform through internal team and external expert review/input; make it accessible for non-experts to maximize opportunities & impact of structure-based drug discovery (SBDD) e.g. coordinate development of internal webpages providing ready access to data for programs; simple app to enable easy review of output from screening algorithms
- Manage platform development with the external team (3+ FTEs)
Identify and exploit synergies across HotSpot drug discovery platform
- Exploit opportunities at interface of wet screening and in silico approaches e.g., next generation DNA-encoded libraries
- Contribute to hotspot-biased chemical library design for proprietary compound collection
- Become internal thought leader for application of deep-learning techniques in target identification and drug discovery
Your background and skills:
- Ph.D. in a relevant scientific discipline with 10+ years of Computational Chemistry experience.
- Track record as part of drug-discovery teams that successfully delivered clinical candidates is required.
- Strong familiarity with a wide range of current computational chemistry software tools from vendors like Schrodinger, OpenEye, Molecular Discovery, CCG and Biovia
- Extensive experience with ligand and structure based computational chemistry activities.
- Molecular design expertise with creativity and the ability to design ligands & libraries; utilize a broad set of tools to evaluate/prioritize ideas.
- Experience in one programming language C/C++/C#, Java or scripting in Perl/Python.
- Working knowledge of synthetic chemistry to enable independent compound design of synthetically tractable targets.
- Proven leadership experience managing projects; must be capable of building computational chemistry as a function within the organization
- Excellent oral and written communication skills and organizational skills are essential
- The ability to work independently while also collaborating across multidisciplinary teams.
- Strong analytical and problem-solving skills and scientific creativity are essential to succeed in this role.
At HotSpot, we have a bold mission to establish new drug discovery paradigm. If this appeals to you, please let us know at email@example.com.
HotSpot is an equal opportunity employer. We celebrate diversity and are committed to creating an inclusive environment for all employees.