Hit-to-Lead
The hit-to-lead (H2L) process is a pivotal phase in drug discovery that involves transforming a “hit” compound, which shows initial activity in a high-throughput or virtual screening, into a “lead” compound with enhanced potency and properties suitable for further development.
This phase requires significant optimization of small molecule hits across multiple aspects to achieve an improved profile in a single candidate compound.
From innovative biology to quality chemistry
The optimization process typically occurs in two major phases. Initially, the H2L process aims to evolve hits into compounds that can be tested for the underlying treatment hypothesis in relevant animal disease models. This is followed by the Lead Optimization phase, which seeks to identify a preclinical candidate suitable for eventual clinical use and commercialization. Optimization is a multidisciplinary effort centered around medicinal chemistry, involving iterative cycles of “design-make-test-analyze”.
The focus is on identifying potential lead compounds with improved properties compared to the initial hit, through various activities such as:
- Structure-Activity Relationship (SAR) studies: Understand how the chemical structure of compounds affects their biological activity.
- Computational modeling: Use molecular modeling, docking studies, and other computational tools to predict the impact of modifications on the hit compound's activity, selectivity, and pharmacokinetic properties.
- Strategic analogs design: Create a focused library of analogs based on the hit compound to explore chemical space and identify modifications that enhance desirable properties.
This set of molecules is synthesized to verify biological activity. Planning and optimizing the synthetic pathway is crucial to produce analogs efficiently and in sufficient quantities, considering chemical tractability and potential scalability for future development.
As data accumulates on hit derivatives, it guides medicinal chemists in further design. A detailed target compound profile, listing all necessary features and properties, ensures technical suitability for achieving the next milestone. This profile determines the assays (or screening cascade) required to test newly generated compounds.
Data accumulated on hit derivatives gradually guide the medicinal chemist in the further design process. A detailed target compound profile, listing all necessary features and properties, ensures technical suitability for achieving the next milestone. This profile determines the assays (or screening cascade) required to test newly generated compounds.
Typical parameters for Hit-to-Lead optimization include:
- potency in (i.) primary screening assay, (ii.) secondary in vitro assay(s)
- selectivity: (i.) off targets, (ii.) orthologues relevant in screening cascade
- phys-chem profile: (i.) solubility, (ii.) lipophilicity, (iii.) …
- ADME profile: (i.) protein binding, (ii.) membrane permeability, (iii.) plasma stability, (iv.) liver microsomal stability
- cellular toxicity (in vitro)
- in vivo pharmacokinetic
Additional items might need to be added depending on project specific aspects. Commercial viability of a project generally depends on generating compounds and associated data to support a solid Intellectual Property (IP) position. Without forestalling the IP strategy of individual clients, our medicinal chemists will support this effort through continuous queries in available patent databases and expert consultancy on securing a path to IP.
Integration and project management
The H2L process benefits from expertise in bioassay technologies, computational and wet chemistry, and a well-developed infrastructure for handling and managing chemical compounds and data. Experienced project management ensures optimal, goal-oriented operation of the multidisciplinary team, often supported by external partners providing key experiments and services.

Axxam provides directly or via well-established partnerships all relevant technical capabilities and expertise to design and execute your hit-to-lead programs.
Deciding for a fully integrated service package ensures a seamless transition from HTS into H2L optimization, no additional logistic or administrative work and an overall efficient project management simplifying your life.