Hits are important starting point in a discovery program. Hits are either provided by client or generated using virtual screen, knowledge based design or HTS using client’s compound library.
Virtual Screening: Computational Chemists leverage the GVK BIO proprietary databases containing over 6 million compounds. These databases capture various properties of compounds including chemical, biological and material science properties and support discovery research for structure mining, focused library design, computational chemistry and SAR analysis.
Knowledge Based Design: GVK BIO’s discovery chemists make use of multi parameter advanced chemical analogue approaches for Hit/Lead Generation and Optimisation based on the known structures which bind to target of interest, target substrate or inhibition of protein-protein interaction.
HTS: GVK BIO does not have proprietary compound collection, but can undertake high throughput screening (HTS) on commercially available libraries or libraries provided by clients.
Qualified hits undergo ADME screening, such as, solubility, logD, CYP interaction, permeability, etc. to understand the liabilities at an early stage.
These hits are further evaluated for lead likeliness such as LiPE plot, optimisation potential (in terms of medicinal chemistry), binding and functional assay. Preliminary SAR is generated by filling the gaps with new molecules or synthesising analogues. These analogues are not only evaluated for their potency (biochemical and cell based) but also assessed for selectivity, efficacy in relevant animal models, PK and early safety. Target relevant pharmacodynamic models are developed to guide SAR development and compound prioritisation for efficacy models. End point is identification of more than one lead series.
One series is prioritised for LO and the other for backup. Apart from potency, PK and efficacy, analogues are assessed for novelty, extended selectivity, efficacy in animal models, safety pharmacology and preclinical toxicity. The goal is identification of pre-clinical candidate(s).