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Multiple virtual screening approaches for finding new hepatitis C virus RNA-dependent RNA polymerase inhibitors: structure-based screens and molecular dynamics for the pursue of new poly pharmacological inhibitors.

ABSTRACT: The RNA polymerase NS5B of Hepatitis C virus (HCV) is a well-characterised drug target with an active site and four allosteric binding sites. This work presents a workflow for virtual screening and its application to Drug Bank screening targeting the Hepatitis C Virus (HCV) RNA polymerase non-nucleoside binding sites. Potential polypharmacological drugs are sought with predicted active inhibition on viral replication, and with proven positive pharmaco-clinical profiles. The approach adopted was receptor-based. Docking screens, guided with contact pharmacophores and neural-network activity prediction models on all allosteric binding sites and MD simulations, constituted our analysis workflow for identification of potential hits. Steps included: 1) using a two-phase docking screen with Surflex and Glide Xp. 2) Ranking based on scores, and important H interactions. 3) a machine-learning target-trained artificial neural network PIC prediction model used for ranking. This provided a better correlation of IC50 values of the training sets for each site with different docking scores and sub-scores. 4) interaction pharmacophores-through retrospective analysis of protein-inhibitor complex X-ray structures for the interaction pharmacophore (common interaction modes) of inhibitors for the five non-nucleoside binding sites were constructed. These were used for filtering the hits according to the critical binding feature of formerly reported inhibitors. This filtration process resulted in identification of potential new inhibitors as well as formerly reported ones for the thumb II and Palm I sites (HCV-81) NS5B binding sites. Eventually molecular dynamics simulations were carried out, confirming the binding hypothesis and resulting in 4 hits.

SUBMITTER: Elhefnawi M

PROVIDER: S-EPMC3521232 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Multiple virtual screening approaches for finding new hepatitis C virus RNA-dependent RNA polymerase inhibitors: structure-based screens and molecular dynamics for the pursue of new poly pharmacological inhibitors.

Elhefnawi Mahmoud M ElGamacy Mohammad M Fares Mohamed M

BMC bioinformatics 20121213

The RNA polymerase NS5B of Hepatitis C virus (HCV) is a well-characterised drug target with an active site and four allosteric binding sites. This work presents a workflow for virtual screening and its application to Drug Bank screening targeting the Hepatitis C Virus (HCV) RNA polymerase non-nucleoside binding sites. Potential polypharmacological drugs are sought with predicted active inhibition on viral replication, and with proven positive pharmaco-clinical profiles. The approach adopted was ...[more]

PMID: 23282180

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Project description:The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer's disease drugs.

Dataset Information

Multiple virtual screening approaches for finding new hepatitis C virus RNA-dependent RNA polymerase inhibitors: structure-based screens and molecular dynamics for the pursue of new poly pharmacological inhibitors.

Publications

Multiple virtual screening approaches for finding new hepatitis C virus RNA-dependent RNA polymerase inhibitors: structure-based screens and molecular dynamics for the pursue of new poly pharmacological inhibitors.

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