Universal Frags2Drugs (uF2D): a proteome-wide in silico fragment-based ligand design tool - Archive ouverte HAL
Communication Dans Un Congrès Année : 2023

Universal Frags2Drugs (uF2D): a proteome-wide in silico fragment-based ligand design tool

Résumé

Computational methods are extensively employed during the initial stages of drug discov- ery process to reduce its duration and cost.(1) Fragment-based drug design (FBDD) prioritizes binding efficiency over global binding affinity. In our previous work, we have developed Frags2Drugs (F2D), an innovative in silico FBDD tool aiming to design novel protein kinase inhibitors.(2) However, its applicability domain is limited solely to protein kinases, restricting its widespread adoption. Furthermore, F2D is based on the alignment of protein kinases, rendering it impractical for proteins belonging to distinct families. Herein, we present Universal Frags2Drugs (uF2D), an enhanced iteration of F2D, which expands its applicability domain to encompass all protein families. The uF2D methodology comprises two distinct components: a fragment repositioning tool and a linker generator. The initial fragment repositioning phase is accomplished through the adaptation and customization of a pre-existing tool, referred to as CrystalDock.(3) On a limited dataset consisting of 314 representative protein-ligand complexes, CrystalDock demonstrates the ability to successfully reposition the entirety of ligand fragments in approxi- mately 90% of the cases. We are currently updating the fragment database with CrystalDock, and evaluating multiple deep learning-based linker generators to incorporate into uF2D. (1) A. V. Sadybekov, V. Katritch, Nature 2023, 616, 673–685. (2) G. Peyrat, C. Bournez, P. Krezel, J.-M. Gally, S. Bourg, S. Aci-S`eche, P. Bonnet, Journal of Medicinal Chemistry, submitted (3) J. D. Durrant, A. J Keywords. Friedman, J. A. McCammon, J. Chem. Inf. Model. 2011, 51, 2573–2580.
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Dates et versions

hal-04737072 , version 1 (15-10-2024)

Identifiants

  • HAL Id : hal-04737072 , version 1

Citer

Xiaojun Mao, Samdani Ansar, Mahesh Velasumy, Samia Aci-Sèche, Pascal Bonnet. Universal Frags2Drugs (uF2D): a proteome-wide in silico fragment-based ligand design tool. SFCi-11 : 11èmes journées de la Société Française de Chémoinformatique, Oct 2023, CAEN, France. ⟨hal-04737072⟩
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