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Up Directory CCL 18.07.18 Head of Computational Chemistry, Cambridge, MA (Req number: 15363)
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Date: Wed Jul 18 13:24:45 2018
Subject: 18.07.18 Head of Computational Chemistry, Cambridge, MA (Req number: 15363)
Head of Computational Chemistry (Req number: 15363)
Full-time role based in Cambridge, MA, USA

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.  

Your motivations:

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 HotSpots 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.

Your role:

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 typical day will include the following activities:

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 Amazons 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:

 -  Ph.D. in a relevant scientific discipline with 12+ years of Computational Chemistry experience.

 -  Strong familiarity with a wide range of current computational chemistry software tools; experience 
    with ligand and structure based computational chemistry activities.

 -  Proven track record as part of drug-discovery teams that successfully delivered clinical candidates
    is desirable

 -   Expert molecular designer with creativity and the ability to design ligands & libraries; utilizes broad
     set of tools to evaluate/prioritize ideas.

 -   A working knowledge of synthetic chemistry to enable independent compound design of 
     synthetically tractable targets.
At HotSpot, we have a bold mission to establish new drug discovery paradigm.  
If this appeals to you, please let us know at iamcurious-,-hotspotthera.com.
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