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Methyl effects on protein-ligand binding.

ABSTRACT: The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38? MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.

SUBMITTER: Leung CS

PROVIDER: S-EPMC3353327 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Methyl effects on protein-ligand binding.

Leung Cheryl S CS Leung Siegfried S F SS Tirado-Rives Julian J Jorgensen William L WL

Journal of medicinal chemistry 20120423 9

The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-en ...[more]

PMID: 22500930

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Project description:OBJECTIVE:Emerging evidence supports a role for epigenetic regulation in the pathogenesis of scleroderma (SSc). We aimed to assess the role of methyl-CpG-binding protein 2 (MeCP2), a key epigenetic regulator, in fibroblast activation and fibrosis in SSc. METHODS:Dermal fibroblasts were isolated from patients with diffuse cutaneous SSc (dcSSc) and from healthy controls. MeCP2 expression was measured by qPCR and western blot. Myofibroblast differentiation was evaluated by gel contraction assay in vitro. Fibroblast proliferation was analysed by ki67 immunofluorescence staining. A wound healing assay in vitro was used to determine fibroblast migration rates. RNA-seq was performed with and without MeCP2 knockdown in dcSSc to identify MeCP2-regulated genes. The expression of MeCP2 and its targets were modulated by siRNA or plasmid. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) using anti-MeCP2 antibody was performed to assess MeCP2 binding sites within MeCP2-regulated genes. RESULTS:Elevated expression of MeCP2 was detected in dcSSc fibroblasts compared with normal fibroblasts. Overexpressing MeCP2 in normal fibroblasts suppressed myofibroblast differentiation, fibroblast proliferation and fibroblast migration. RNA-seq in MeCP2-deficient dcSSc fibroblasts identified MeCP2-regulated genes involved in fibrosis, including PLAU, NID2 and ADA. Plasminogen activator urokinase (PLAU) overexpression in dcSSc fibroblasts reduced myofibroblast differentiation and fibroblast migration, while nidogen-2 (NID2) knockdown promoted myofibroblast differentiation and fibroblast migration. Adenosine deaminase (ADA) depletion in dcSSc fibroblasts inhibited cell migration rates. Taken together, antifibrotic effects of MeCP2 were mediated, at least partly, through modulating PLAU, NID2 and ADA. ChIP-seq further showed that MeCP2 directly binds regulatory sequences in NID2 and PLAU gene loci. CONCLUSIONS:This study demonstrates a novel role for MeCP2 in skin fibrosis and identifies MeCP2-regulated genes associated with fibroblast migration, myofibroblast differentiation and extracellular matrix degradation, which can be potentially targeted for therapy in SSc.

Project description:The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and (ii) the binding of chromanol 293B ligand and its derivatives into the complex. The results reveal that interactions between KCNQ1 with KCNE1 causes a pore constriction in the former, which in-turn forms small energetic barriers in the ion-permeation pathway. These findings correlate with the previous experimental reports that interactions of KCNE1 dramatically slows the activation of KCNQ1. Upon ligand-binding onto the complex, the energy-barriers along ion permeation path are more pronounced, as expected, therefore, requiring higher force in our steered-MD simulations. Nevertheless, pulling the ion when a weak blocker is bound to the channel does not necessitate high force in SMD. This indicates that our SMD simulations have been able to discern between strong and week blockers and reveal their influence on potassium ion permeation. The findings presented here will have some implications in understanding the potential off-target interactions of the drugs with the KCNQ1/KCNE1 channel that lead to cardiotoxic effects.

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Methyl effects on protein-ligand binding.

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Methyl effects on protein-ligand binding.

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