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Hit to Lead Discovery

Hit to Lead (H2L) Discovery of Novel Actives for a Target

Hit to Lead (H2L) identification is a core competency of pharmaceutical companies. This process involves identifying new molecules with desired activity against a specific target, which are then optimized in an iterative cycle.

This is often the stage where the project needs to be infused with innovation and untapped IP. Only molecules that are previously unknown hold the potential for financial success for the company and to provide an extended therapeutic benefit.

On this page, we elaborate on different computational methods to mine for chemically novel molecules that can become drug candidates.

Docking Approaches to Mine for Binding Candidates

The hit to lead identification step can significantly be augmented by computational approaches that predict the binding modes of molecules and coupled them to a docking score. The docking score is a numerical value that reflects the interaction complementary between target structure and a ligand. Therefore, compounds with a higher docking score are more likely to interact/bind to a target structure, which allows a prefiltering of larger molecule sets to focus on the most promising candidates for in vitro evaluation.
Prior to the hit to lead step, virtual screenings are usually run to reduce the numbers of compounds to be tested.

Advantages of docking approaches is to bring chemically diverse molecules to the surface and that the method can be applied across a wide range of targets.
Additionally, using filters before docking—such as pharmacophore constraints to secure key interactions within the binding site—or applying filters post-docking, including molecular torsions, clash checks, and ligand efficiency, further improves the quality and accumulation of viable hits.
BioSolveIT software for docking:
  • SeeSAR: Visual, drug design dashboard for computational and medicinal chemists.
    SeeSAR's Docking Mode helps you to predict the binding mode for a single ligand or a whole molecule collection. Furthermore, you can assess the quality of the results given SeeSAR's intuitive color-coding to select candidates to follow up with.
    The external Docking Mode performs the calculations on separate hardware and loads the results back into SeeSAR once they have finished. This enables the convenient and efficient processing of even large molecule libraries as in high-performance computing.
  • Chemical Space Docking™: (as SeeSAR's Space Docking Mode)
    C-S-D is a the next generation of structure-based virtual screening. In this innovative approach, ultra-vast Chemical Spaces, containing billions or even trillions of entries can be screened for the promising candidates to bind at the target structure.
Command-line tools for docking:
  • FlexX: Docking algorithm.
  • HYDE: De-solvation-aware scoring algorithm.

Ligand-Based Screening in Hit to Lead Campaigns

Ligand-based drug design (LBDD) enables the proposal of potential binders without the need of the target’s 3D structure. Instead, LBDD relies on known binders that exhibit the desired activity. Using these reference compounds, a library of molecules is screened for those with similar molecular properties and functionalities, identifying promising candidates based on their likeness to effective binders.
For this purpose, BioSolveIT develops Chemical Space exploration software that is able to retrieve compounds tailored to the aims of the project from ultra-large compounds collections: The Chemical Spaces.
BioSolveIT software for Chemical Space exploration:
  • infiniSee: Chemical Space navigation platform with a graphical user interface.
    infiniSee retrieves relevant chemistry from ultra-large Chemical Spaces containing billions or even trillions of compounds based on their similarity to a query compound. Results are synthetically accessible per design in one or two steps and, in the case of our partners' Chemical Spaces, can be ordered directly to your table.
  • infiniSee xREAL: Exclusive platform to screen Enamine's largest compound catalog featuring trillions of compounds.
    infiniSee xREAL contains all features of infiniSee and supports all three Chemical Space exploration search modes.
Command-line tools for Chemical Space exploration:
  • FTrees: Pharmacophore-based similarity screen. Algorithm behind the Scaffold Hopper Mode.
  • SpaceLight: Retrieves close analogs based on molecular fingerprints. Algorithm behind the Analog Hunter Mode.
  • SpaceMACS: Performs maximum common substructure searches, as well as exact substructure mining. Algorithm behind the Motif Matcher Mode.

Discovering Candidates with 3D Ligand-Based Methods

Hit to lead campaigns can also profit from 3D ligand-based approaches.
Here, a template molecule is used on a compound library. The entries are aligned with the aim to match similar molecular features and fit the shape of the query. Compounds displaying similar arrangement of functionalities have a higher propbability of displaying similar biological activities at the target.

BioSolveIT software for 3D LBDD:
  • SeeSAR's Similarity Scanner Mode: Ligand-based virtual screening.
Command-line tools for 3D LBDD:
  • FlexS: 3D compound alignment.

Further readings

Hit discovery and hit-to-lead approaches.
Keserű, G.M.; Makara, G.M.
Drug Discovery Today 2006, 11 (15-16), 741-748.
Hit and lead generation: beyond high-throughput screening.
Bleicher, K.H.; Böhm, H.; Müller, K.; Alanine, A.I.
Nature Reviews Drug Discovery 2003, 2 (5), 369-378.
Early phase drug discovery: Cheminformatics and computational techniques in identifying lead series.
Duffy, B.C.; Zhu, L.; Decornez, H.; Kitchen, D.B.
Bioorganic & Medicinal Chemistry 2012, 20 (18), 5324-5342.

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