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Last update 23 Jan 2025

MECR

Last update 23 Jan 2025

Basic Info

Synonyms

2-enoyl thioester reductase, CGI-63, Enoyl-[acyl-carrier-protein] reductase, mitochondrial

+ [12]

Introduction

Catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (fatty acid synthesis type II). Fatty acid chain elongation in mitochondria uses acyl carrier protein (ACP) as an acyl group carrier, but the enzyme accepts both ACP and CoA thioesters as substrates in vitro. Displays a preference for medium-chain over short- and long-chain substrates (PubMed:18479707, PubMed:12654921, PubMed:27817865). May provide the octanoyl chain used for lipoic acid biosynthesis, regulating protein lipoylation and mitochondrial respiratory activity particularly in Purkinje cells (By similarity).

Drugs associated with MECR

Afabicin diolamine

Target

MECR

Mechanism

MECR inhibitors

Active Org.

Debiopharm International SA [+1]

Originator Org.

GSK Plc

Active Indication

Arthritis [+4]

Inactive Indication

Bone Diseases, Infectious [+3]

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

AFN-1252

Target

MECR

Mechanism

MECR inhibitors

Active Org.

GSK Plc

Originator Org.

GSK Plc

Active Indication

Skin and skin structure infections

Inactive Indication

Abscess [+5]

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Nilofabicin

Target

MECR

Mechanism

MECR inhibitors

Active Org.

CG Invites Co., Ltd.

Originator Org.

CG Invites Co., Ltd.

Active Indication

MRSA - Methicillin resistant Staphylococcus aureus infection

Inactive Indication

Skin and skin structure infections [+1]

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MECR

NCT05393856

/ CompletedPhase 1

CG-549 Tablet Pharmacokinetics Study: An Open-label, Single Ascending Dose Study to Evaluate the Safety and Pharmacokinetics of a Tablet Formulation of CG-549 in Healthy Subjects

This will be an open label, crossover, single dose study consisting of 2 parts (Part A and Part B) in a total of 24 healthy male and female subjects.

Start Date23 Sep 2019

Sponsor / Collaborator

CG Invites Co., Ltd.

NL-OMON48209

/ CompletedNot Applicable

An open-label, single ascending dose study to evaluate the safety and pharmacokinetics of a tablet formulation of CG-549 in healthy subjects - CG-549 tablet pharmacokinetics study

Start Date23 Sep 2019

Sponsor / Collaborator

CG Invites Co., Ltd.

NCT03723551

/ RecruitingPhase 2

Randomized Open-label Active-controlled Study to Assess the Safety, Tolerability, and Efficacy of Afabicin IV/Oral in the Treatment of Patients With Bone or Joint Infection Due to Staphylococcus

This is a randomized, active-controlled, open-label study to assess the safety, tolerability and efficacy of Afabicin in the treatment of participants with bone or joint infection due to Staphylococcus aureus [both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA)] and/or coagulase-negative staphylococci (CoNS) and to compare it to standard of care (SOC).

Start Date20 Feb 2019

Sponsor / Collaborator

Debiopharm International SA

100 Clinical Results associated with MECR

100 Translational Medicine associated with MECR

0 Patents (Medical) associated with MECR

508

Literatures (Medical) associated with MECR

01 Mar 2025·Current Computer-Aided Drug Design

Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights

Article

Author: Dharamsi, Abhay ; Tripathi, Rati Kailash Prasad ; Patel, Vaishali Pavalbhai

Background:Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities.Objective:To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA.Methods:The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties.Results:Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability.Conclusion:Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

01 Feb 2025·Mini-Reviews in Medicinal Chemistry

Development of Mycobacterium tuberculosis Enoyl Acyl Reductase (InhA) Inhibitors: A Mini-Review

Article

Author: Tailor, Navin Kumar ; Guarve, Kumar ; Grewal, Ajmer Singh ; Deswal, Geeta

This review article delves into the critical role of Enoyl acyl carrier protein reductase (InhA; ENR), a vital enzyme in the NADH-dependent acyl carrier protein reductase family, emphasizing its significance in fatty acid synthesis and, more specifically, the biosynthesis of mycolic acid. The primary objective of this literature review is to elucidate diverse scaffolds and their developmental progression targeting InhA inhibition, thereby disrupting mycolic acid biosynthesis. Various scaffolds, including thiourea, piperazine, thiadiazole, triazole, quinazoline, benzamide, rhodanine, benzoxazole, and pyridine, have been systematically explored for their potential as InhA inhibitors. Noteworthy findings highlight thiadiazole and triazole derivatives, demonstrating promising IC50 values within the nanomolar concentration range. The review offers comprehensive insights into InhA's structure, structure-activity relationships, and a detailed overview of distinct scaffolds as effective inhibitors of InhA.

01 Dec 2024·Journal of Biological Chemistry

Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency

Article

Author: Perry, Ava ; Bick, Nolan R ; Dreishpoon, Margaret B ; Rogachevskaya, Anna ; Tsvetkov, Peter ; Fleming, Mark D ; Bottomley, Sylvia S ; Ducamp, Sarah

Protein lipoylation, a vital lysine post-translational modification, plays a crucial role in the function of key mitochondrial tricarboxylic acid cycle enzymatic complexes. In eukaryotes, lipoyl post-translational modification synthesis occurs exclusively through de novo pathways, relying on lipoyl synthesis/transfer enzymes, dependent upon mitochondrial fatty acid and Fe-S cluster biosynthesis. Dysregulation in any of these pathways leads to diminished cellular lipoylation. Efficient restoration of lipoylation in lipoylation deficiency cell states using either chemical or genetic approaches has been challenging because of pathway complexity and multiple upstream regulators. To address this challenge, we explored the possibility that a bacterial lipoate protein ligase A (lplA) enzyme, which can salvage free lipoic acid bypassing the dependency on de novo synthesis, could be engineered to be functional in human cells. Overexpression of the engineered lplA in lipoylation null cells restored lipoylation levels, cellular respiration, and growth in low glucose conditions. Engineered lplA restored lipoylation in all tested lipoylation null cell models, mimicking defects in mitochondrial fatty acid synthesis (MECR KO), Fe-S cluster biosynthesis (BOLA3 KO), and specific lipoylation-regulating enzymes (FDX1 [ferredoxin 1], LIAS [lipoyl synthase], and LIPT1 [lipoyl (octanoyl) transferase 1] KOs). Furthermore, we describe a patient with a homozygous c.212C>T variant LIPT1 with a previously uncharacterized syndromic congenital sideroblastic anemia. K562 erythroleukemia cells engineered to harbor this missense LIPT1 allele recapitulate the lipoylation-deficient phenotype and exhibit impaired proliferation in low glucose that is completely restored by engineered lplA. This synthetic approach offers a potential therapeutic strategy for treating lipoylation disorders.

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