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In silico fragment-based drug design with SEED


Marchand, Jean-Rémy; Caflisch, Amedeo (2018). In silico fragment-based drug design with SEED. European journal of medicinal chemistry, 156:907-917.

Abstract

We report on two fragment-based drug design protocols, SEED2XR and ALTA, which start by high-throughput docking. SEED2XR is a two-stage protocol for fragment-based drug design. The first stage is in silico and consists of the automatic docking of 10-10 fragments using SEED, which requires about 1 s per fragment. SEED is a docking software developed specifically for fragment docking and binding energy evaluation by a force field with implicit solvent. In the second stage of SEED2XR, the 10-10 fragments with the most favorable predicted binding energies are validated by protein X-ray crystallography. The recent applications of SEED2XR to bromodomains demonstrate that the whole SEED2XR protocol can be carried out in about a week of working time, with hit rates ranging from 10% to 40%. Information on fragment-target interactions generated by the SEED2XR protocol or directly from SEED docking has been used for the discovery of hundreds of hits. ALTA is a computational protocol for screening which identifies candidate ligands that preserve the interactions between the optimal SEED fragments and the protein target. Medicinal chemistry optimization of ligands predicted by ALTA has resulted in pre-clinical candidates for protein kinases and bromodomains. The high-throughput, very low cost, sustainability, and high hit rate of the SEED-based protocols, unreachable by purely experimental techniques, make them perfectly suitable for both academic and industrial drug discovery research.

Abstract

We report on two fragment-based drug design protocols, SEED2XR and ALTA, which start by high-throughput docking. SEED2XR is a two-stage protocol for fragment-based drug design. The first stage is in silico and consists of the automatic docking of 10-10 fragments using SEED, which requires about 1 s per fragment. SEED is a docking software developed specifically for fragment docking and binding energy evaluation by a force field with implicit solvent. In the second stage of SEED2XR, the 10-10 fragments with the most favorable predicted binding energies are validated by protein X-ray crystallography. The recent applications of SEED2XR to bromodomains demonstrate that the whole SEED2XR protocol can be carried out in about a week of working time, with hit rates ranging from 10% to 40%. Information on fragment-target interactions generated by the SEED2XR protocol or directly from SEED docking has been used for the discovery of hundreds of hits. ALTA is a computational protocol for screening which identifies candidate ligands that preserve the interactions between the optimal SEED fragments and the protein target. Medicinal chemistry optimization of ligands predicted by ALTA has resulted in pre-clinical candidates for protein kinases and bromodomains. The high-throughput, very low cost, sustainability, and high hit rate of the SEED-based protocols, unreachable by purely experimental techniques, make them perfectly suitable for both academic and industrial drug discovery research.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:17 July 2018
Deposited On:04 Sep 2018 13:43
Last Modified:05 Sep 2018 07:32
Publisher:Elsevier
ISSN:0223-5234
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ejmech.2018.07.042
PubMed ID:30064119

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