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MolSoft ICM RNA Modeling and Lead Discovery

Ligand Guided RNA Modeling using MolSoft ICM

A publication in Nature Chemical Biology describes the discovery of a potent small molecule which has the potential to be used to treat Spinal Muscular Atrophy (SMA) a debilitating motor neuron disease. The disease is caused by a deficiency of Survival of Motor Neuron (SMN) gene which is the most common cause of mortality in children. The pyridazine class of compounds described in this paper enhance SMN2 splicing which elevates full-length SMN protein. It is proposed that the small molecule modulators enhance binding of U1 snRNP to the SMN2 exon 7 5'ss. Using MolSoft's ICM Alibero Method, scientists at Novartis Institute of Biomedical Research were able to model the binding mode of the molecule with RNA (See Figure- left). To model the flexibility of RNA a population of 150 RNA models was generated and the Alibero method was able to determine the model that best separated known binders from non-binders. On the basis of this model they were able to hypothesize that the small molecules enhance the stabilization of the RNA duplex in the 1A bulge major groove.

RNA Docking and Screening - de novo RNA inhibitor discovery using MolSoft ICM.

The Al-Hashimi laboratory at Duke University have successfully used ICM for docking of small molecules to an ensemble of RNA structures. Their paper in Nature Chemical Biology describes how they docked and screened small molecules to RNA NMR/MD models of the transactivation response element (TAR) from the human immunodeficiency type 1 virus (HIV-1) using ICM-VLS. They discovered six new chemicals that bind to TAR with exceptional activity and also inhibit its interaction with Tat peptide.

First RNA Virtual Screening Success

One of the first Virtual Screening success stories using ICM-VLS reported the discovery of ligands to the TAR RNA structure which inhibited Tat-TAR interaction (see Filikov et al ). A database of 153,000 chemicals was screened against TAR and 8 compounds were chosen for experimental testing. From the eight tested two were shown in assays to inhibit the Tat-TAR interaction (publication

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