Dataset Information

LICHEM 1.1: Recent Improvements and New Capabilities.

ABSTRACT: The QM/MM method has become a useful tool to investigate various properties of complex systems. We previously introduced the layered interacting chemical models (LICHEM) package to enable QM/MM simulations with advanced potentials by combining various (unmodified) QM and MM codes ( J. Comp. Chem., 2016, 37, 1019). LICHEM provides several capabilities such as the ability to use polarizable force fields, such as AMOEBA, for the MM environment. Here, we describe an updated version of LICHEM (v1.1), which includes several new functionalities including a new method to account for long-range electrostatic effects in QM/MM (QM/MM-LREC), a new implementation for QM/MM with the Gaussian electrostatic model (GEM), and new capabilities for path optimizations using the quadratic string model (QSM) coupled with restrained MM environment optimization.

SUBMITTER: Gokcan H

PROVIDER: S-EPMC6526954 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

LICHEM 1.1: Recent Improvements and New Capabilities.

Gökcan Hatice H Vázquez-Montelongo Erik Antonio EA Cisneros G Andrés GA

Journal of chemical theory and computation 20190402 5

The QM/MM method has become a useful tool to investigate various properties of complex systems. We previously introduced the layered interacting chemical models (LICHEM) package to enable QM/MM simulations with advanced potentials by combining various (unmodified) QM and MM codes ( J. Comp. Chem., 2016, 37, 1019). LICHEM provides several capabilities such as the ability to use polarizable force fields, such as AMOEBA, for the MM environment. Here, we describe an updated version of LICHEM (v1.1), ...[more]

PMID: 30908049

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Project description:Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A(1), A(2A), A(2B) and A(3) (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A(2B) AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A(2B) AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A(2B) AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N (6)-, C(2)-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N'-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-beta-D-ribofuranuronamide (19, hA(1) K (i) = 1050 nM, hA(2A) K (i) = 1550 nM, hA(2B) EC(50) = 82 nM, hA(3) K (i) > 5 muM) and its 2-chloro analogue 23 (hA(1) K (i) = 3500 nM, hA(2A) K (i) = 4950 nM, hA(2B) EC(50) = 210 nM, hA(3) K (i) > 5 muM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA(2B) AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA(1), hA(2A), hA(3) EC(50) > 10 muM; hA(2B) EC(50) = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.

Dataset Information

LICHEM 1.1: Recent Improvements and New Capabilities.

Publications

LICHEM 1.1: Recent Improvements and New Capabilities.

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