[NMR paper] HT-SuMD: making molecular dynamics simulations suitable for fragment-based screening. A comparative study with NMR.

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HT-SuMD: making molecular dynamics simulations suitable for fragment-based screening. A comparative study with NMR.

Related Articles HT-SuMD: making molecular dynamics simulations suitable for fragment-based screening. A comparative study with NMR.

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1-14

Authors: Ferrari F, Bissaro M, Fabbian S, De Almeida Roger J, Mammi S, Moro S, Bellanda M, Sturlese M

Abstract
Fragment-based lead discovery (FBLD) is one of the most efficient methods to develop new drugs. We present here a new computational protocol called High-Throughput Supervised Molecular Dynamics (HT-SuMD), which makes it possible to automatically screen up to thousands of fragments, representing therefore a new valuable resource to prioritise fragments in FBLD campaigns. The protocol was applied to Bcl-XL, an oncological protein target involved in the regulation of apoptosis through protein-protein interactions. Initially, HT-SuMD performances were validated against a robust NMR-based screening, using the same set of 100 fragments. These independent results showed a remarkable agreement between the two methods. Then, a virtual screening on a larger library of additional 300 fragments was carried out and the best hits were validated by NMR. Remarkably, all the in silico selected fragments were confirmed as Bcl-XL binders. This represents, to date, the largest computational fragments screening entirely based on MD.


PMID: 33115279 [PubMed - in process]



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