Last update 01 Nov 2024

INHA

Last update 01 Nov 2024

Basic Info

Synonyms

INHA, Inhibin alpha chain, inhibin subunit alpha

Introduction

Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland. Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition. Inhibins appear to oppose the functions of activins.

Drugs associated with INHA

InhA inhibitor (Masaryk University)

Target

INHA

Mechanism

INHA inhibitors

Active Org.

Tongji University [+1]

Originator Org.

Palacky University

Active Indication

Mycoses [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with INHA

100 Translational Medicine associated with INHA

0 Patents (Medical) associated with INHA

1,844

Literatures (Medical) associated with INHA

01 Dec 2024·European Journal of Medicinal Chemistry

Design and synthesis of Thieno[3, 2-b]pyridinone derivatives exhibiting potent activities against Mycobacterium tuberculosis in vivo by targeting Enoyl-ACP reductase

Article

Author: Liang, Lihong ; Hu, Yangbo ; Zhang, Niuniu ; Liu, Zhiyong ; Chen, Xinwen ; Li, Jun ; Zhang, Tianyu ; Zhou, Yihuan ; Chen, Jie ; Zha, Qin

In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5-1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T_1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents.

01 Nov 2024·Microbial Pathogenesis

Halogenated chalcones against Mycobacterium tuberculosis targeting InhA: Rational design, in silico and in vitro evaluation

Article

Author: Manoharadas, Salim ; Govindasamy, Rajakumar ; Thiruvengadam, Muthu ; Viswanathan, Dhivya ; Dhivya, L S ; Pandiaraj, Saravanan ; Dhivya, L.S.

A library of 25-series compounds was designed against Mycobacterium Tuberculosis (M.tb) to identify novel antitubercular drugs. In silico inhibition of InhA, an essential component of FAS-II, was successfully achieved. The drug ability, lead-likeness, and toxicity of the compounds were assessed using Swiss ADME, pkCSM, and Osiris Property Explorer, which revealed the potential for drug development of chalcone compounds. Through in silico research, it was confirmed that toxic-free compounds could bind to InhA. It was found that all of the compounds bind to InhA with binding affinities ranging from -7.78 to -10.29 kcal/mol^-1 which is higher than the reference standard Isoniazid and Pyrazinamide. The top five compounds were synthesized from 15 toxic-free compounds. The structural characteristics of the compounds were determined using IR, NMR, and mass spectrometry techniques. These findings indicate that these substances are competitive, reversible, and specific InhA inhibitors of InhA. using the Alamar Blue assay method (H37RV, ATCC No. 27294), the in vitro anti-mycobacterial activity of each of the synthesized compounds against M.tb was evaluated. The two most powerful compounds were (2E)-3-[4-(benzyloxy)-3,5-dimethylphenyl] and (2E)-1-(3,5-dibromophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one. In the MABA Assay, the MIC for 1-(3,5-dibromophenyl) prop-2-en-1-one was 6.25 μg/ml.

12 Oct 2024·Journal of Biomolecular Structure and Dynamics

Identification of potential inhibitors of Mtb InhA: a pharmacoinformatics approach

Article

Author: Kamera, Sreelatha ; Sharma, Vishnu Kumar ; Prasad V., Bharatam ; Garlapati, Achaiah

The emergence of superbugs of multi-drug resistant (MDR/RR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb) strains at a faster rate is posing a serious threat to Tuberculosis (TB) control worldwide. Mtb enoyl-acyl carrier protein reductase (InhA) is a well-established target of the front-line anti-TB prodrug Isoniazid (INH), which requires activation by Catalase-peroxidase enzyme (KatG) in order to inhibit InhA enzyme, that is crucial for the biosynthesis of the mycobacterial cell wall. Currently, due to widespread resistance to this drug, it is necessary to identify new clinical candidates that directly inhibit InhA enzyme and do not require activation by KatG, thereby circumventing most of the resistance mechanisms. In the present study, high-throughput virtual screening of ASINEX database was carried out to identify potential direct inhibitors of Mtb InhA. Best twenty compounds with good binding energies ranging between -12.36 and -9.27 kcal/mol were selected as promising virtual screening hits. These molecules were subjected to ADME study followed by toxicity prediction. Finally, four top-ranked molecules which are structurally diverse and possess best binding affinity than the co-crystalized ligand have been chosen for MD simulation studies followed by MM-GBSA analysis to validate and ensure the stability of hits in the active site of the enzyme. Based on the 100 ns MD simulation studies and binding free energy estimates, three hit molecules B244, B369, and B310 could be considered as potential inhibitors for Mtb InhA, which are likely to be potent against INH-resistant Mtb strains after successful experimental validation.Communicated by Ramaswamy H. Sarma.

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INHA

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