DMTA lead optimization: Where science meets project management

Posted by
on 31 10 2023

Hit identification and lead optimization are complex missions in drug discovery, as the number of promising compounds that can be theoretically identified or created are magnitudes greater than those that can be practically synthesized and tested. This complexity requires efficient project management to prioritize ongoing activities and guide teams towards achieving a clinical candidate.

From hit identification to optimized leads

The mission starts with several complex steps, each of which plays a key role in the transformation of bioactive compounds (known as "hits") into viable drug candidates (often referred to as “leads”). When a hit compound is identified, researchers aim to enhance its properties to make it a more promising candidate for drug development. The process focuses on the systematic refinement of the compound to improve their efficacy, safety, and overall suitability in multiple Design-Make-Test-Analyze (DMTA) cycles. This process can increase a compound's binding affinity to a target protein, improve its metabolic stability, enhance its solubility, and fine-tune its pharmacokinetic properties. These improvements are not just numbers on paper; they translate into real-world benefits by making the drug more effective, safer, and easier to administer. 

The impact of hit-to-lead and lead optimization processes goes beyond the laboratory. It slashes development risks: roughly only 15% of the compounds in the process advance into clinical trials, preventing the expense of hundreds of millions of dollars towards dead ends1,2. It also shortens development timelines, allowing a potential drug to advance to clinical trials faster than it otherwise would. In terms of cost-efficiency, consider this: the price of bringing a drug to market can cost billions. However, by conducting hit-to-lead and lead optimization with accuracy and diligence, this cost can be substantially reduced. The cost savings can be in the hundreds of millions, a significant factor for pharmaceutical companies, and it can also make drugs more affordable for patients. The goal behind these efforts is to not only be more cost-effective but also to gain a competitive edge, enabling companies to bring their innovative treatments to market and secure patents before competitors.

Moving beyond the science - Efficient project management

The transition from a promising hit compound to a viable drug candidate does not rely on science and technology alone. It necessitates effective collaboration among multidisciplinary teams, which consists of medicinal chemists, biologists, computational experts, and project managers. Collaboration, in this context, becomes just as important as using cutting-edge technologies for effective lead optimization.

Furthermore, successful compound optimization also relies on efficient project management. Multiple tasks, such as hypothesis creation, compound design, synthesis, assay data requesting and preparation, as well as data analysis, must be executed smoothly. Project managers need to allocate resources, track progress, and ensure that every aspect of the optimization process is on track. They prioritize all ongoing activities, such as compound design and synthesis, assay data requests, and analysis of results. The ability to make informed decisions on budget allocation, Full-Time Equivalents (FTEs), and assay capabilities can make the difference between a successful project and a costly setback.

In the context of compound optimization, it's worth noting that while scientific aspects are considered essential, efficient task prioritization and resource management are equally important for seamless project execution. This necessitates the coordinated management of diverse tasks and the allocation of resources to meet project goals. 

With its innovative features and capabilities, such as the Kanban board for keeping track of progress of any of the hypothesis, design set, compound and starting material levels, Chemaxon’s Design Hub is engineered to make the compound design/compound optimization process as well as collaboration and information sharing within a drug discovery project smooth.

Read our Showcase document on how to effortlessly design and optimize your compounds in a collaborative fashion with Design Hub.


1.,Bunnage ME. Getting pharmaceutical R&D back on target. Nature chemical biology. 2011. June;7(6):335–9. 10.1038/nchembio.581 [PubMed] [CrossRef] [Google Scholar]
2.,Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nature reviews Drug discovery. 2015. July;14(7):475–86. 10.1038/nrd4609 [PubMed] [CrossRef] [Google Scholar]