Drug Discovery Explained

How are life-saving drugs discovered?

Join DNDi researcher and series host Fanny Escudié to learn more about how scientists are using the most advanced technologies to improve the lives of millions of neglected patients around the world.

Episodes

Episode 1
What are host-directed therapies?

Episode 2
What is high-throughput screening?

Episode 3
What is lead optimization?

Coming soon

Episode 4
What are biomarkers?

Episode 3

The magic of lead optimization: how researchers design molecules to treat neglected diseases

'How do we make sure a molecule is efficacious and safe enough to be given to a human for the first time? This is the fundamental challenge of lead optimization, a crucial step of the drug discovery process,’ says Jadel Müller Kratz, DNDi’s Head of Discovery and R&D Partnerships.  

In our previous episode, we explained how researchers identify promising molecules in huge libraries that can contain millions of compounds. These promising molecules – called ‘hits’ – have the potential to become medicines against a specific disease.  

But hit molecules are far from perfect. Some can be toxic to organs; others are cleared too quickly by the body, without enough time to kill the parasites or viruses that cause the disease.

A hit molecule never has the exact profile we want. It never happens that a hit directly becomes a medicine.’  
Jadel Kratz

The purpose of lead optimization is therefore to refine these imperfect hits until researchers obtain one or several molecules – called ‘leads’ – that will meet the high standards required for the next stages of drug development, including clinical trials with humans. 

Jadel Müller Kratz, Head of Discovery and R&D Partnerships at DNDi

Jadel Müller Kratz, Head of Discovery and R&D Partnerships at DNDi

Luiza Cruz, Drug Discovery Coordinator at DNDi

Luiza Cruz, Drug Discovery Coordinator at DNDi

We want a molecule that is efficient, has no harmful side effects, is safe to take, stays stable in the body, and is not too complex to synthetize so the future medicine will be affordable. The list is long!’  
Luiza Cruz, Drug Discovery Coordinator at DNDi

All these desired characteristics are included in a document we call the target candidate profile (TCP) – a detailed list of the ideal molecule’s characteristics.’ 

To give to the future medicine the properties they are looking for, scientists carefully tweak the molecule’s structure, adding and removing parts.  

This is a bit like adding and removing LEGO bricks to a construction. For example, we will add a carbon part on one side of the molecule, remove a phenyl part, and so on,’ adds Jadel. ‘In this process, we will design hundreds, even thousands of different molecules with different biological properties.’ 

From a ‘hit’ molecule to a good pre-clinical candidate

From a ‘hit’ molecule to a good pre-clinical candidate

The art of molecular tweaking: playing LEGO in the lab 

Researchers will design hundreds of variations of the initial hit on their computers, synthetize these molecules in actual physical form, and then test them in vitro, in laboratories, generating in the process a wealth of data that will help them continue their meticulous tweaking work. 

Based on these results obtained from multiple assays, we have ways to determine which part of the molecule affects properties such as chemical stability, solubility in water, activity against a parasite, et cetera,’ explains Luiza. ‘For example, one component might be great for potency, but bad for stability. A CF3 group might cause toxicity. The challenge is to solve one problem without creating another one.’ 

This iterative, trial-and-error process is the basis to understand structure-activity relationships (SAR) – a key concept in medicinal chemistry. By studying how different chemical modifications influence a molecule’s properties, researchers can make informed decisions about which changes to pursue. 

Example of molecules and their different properties that influence the structure-activity relationship

Example of molecules and their different properties that influence the structure-activity relationship

This work is all the more challenging because molecules are 3D structures, and their shapes can be difficult to predict. A molecule acts against a parasite when a part of its three-dimensional structure fits perfectly into a specific target within the parasite or virus – like a key fitting into a lock. Once the molecule attaches to this biological target, it blocks a specific function, ultimately inactivating the parasite.  

In the lead optimization phase, researchers can generate up to 2,000 compounds over the course of one to three years. They will not only find an ideal candidate that will be tested in safety studies before going into clinical trials but also identify ‘backups’ that can be used if, for some reason, the best candidate does not pass the next stages of the drug development process. 

Scientist working on the synthesis and purification of a compound

Scientist working on the synthesis and purification of a compound

Collaboration in drug discovery: The LOLA network in Latin America 

The delicate work of lead optimization requires a wide variety of expertise. This is why, in Latin America, DNDi launched the LOLA (Lead Optimization Latin America) network. Established in 2013, the partnership includes research institutions, universities, and pharmaceutical companies based in Latin American and focused on drug discovery for neglected tropical diseases like leishmaniasis and Chagas disease. 

We have a wealth of knowledge about these diseases in endemic regions, so DNDi is working to tap into these resources,’ explains Jadel, who is based in Brazil, along with Luiza.

We started small, but now we have four working core units with the capacity to conduct hit-to-lead projects in the region and are connected globally, which is quite nice. Together, we have trained scientists, transferred technology, and even secured local funding.’ 

As a result, LOLA partners have generated hundreds of optimized molecules, established new discovery platforms, and published several articles in scientific journals. But finding a drug candidate for Chagas disease that can be tested in humans remains an immense challenge. 

The challenges of Chagas disease drug discovery 

Developing a new medicine for Chagas disease is notoriously difficult. Despite being discovered over 100 years ago, many aspects of the disease remain poorly understood. The parasite responsible for the disease can hide for years, sometimes decades, in the human body and can infect different cell types and different tissues, like the skin, fat, brain, or heart. The disease progresses very slowly, and people living with the infection can remain asymptomatic for decades. 

For acute diseases that kill fast, a slightly toxic drug might be acceptable if people would otherwise die without treatment. But for Chagas, which can take decades to manifest, we need a drug that is exceptionally safe and that kills all the parasites in the patient’s body. That is a very high bar for us in drug discovery,’ says Jadel. 

Another major challenge lies in assessing treatment success: the parasites that cause Chagas disease appear only minimally in the bloodstream of affected people, which makes it very difficult to confirm whether the medicine being tested has completely wiped them out from their body.

(DNDi and partner researchers recently made a breakthroughiin identifying ‘biomarkers’ that could assess treatment response and may solve this issue – more details soon in an upcoming Drug Discovery Explained episode!) 

Apart from these serious scientific hurdles, Chagas disease drug discovery researchers face another prevailing challenge: financial support for their early-stage research has long been lacking. 

After compounds are available, the team conduct multiple experiments at the laboratories.

After compounds are available, the team conduct multiple experiments at the laboratories.

A call for open science and collaboration on Chagas 

To accelerate research, DNDi launched Open Chagas in 2024, an initiative that promotes open collaboration in drug discovery. 

‘We need to share knowledge and tools. Too much research is duplicated because information isn’t shared enough. With Open Chagas, we invite researchers to join us, share their findings, receive feedback, and even generate free experimental data.’ 
Jadel Kratz

The ultimate goal? To work together to finally find a safe, effective, and accessible cure for Chagas disease. ‘We must find better treatments for Chagas. If you are also working on this disease, please join us!’ 

DNDi logo

The Drugs for Neglected Diseases initiative (DNDi) is an international non-profit research and development organization that discovers, develops, and delivers safe, effective, and affordable treatments for neglected patients.