Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents

Veeravarapu, Hymavathi; Malkhed, Vasavi; Mustyala, Kiran Kumar; Vadija, Rajender; Malikanti, Ramesh; Vuruputuri, Uma; Muthyala, Murali Krishna Kumar

doi:10.1007/s11030-020-10107-0

Cited by 14 publications

(11 citation statements)

References 48 publications

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“…The IR spectra of the compounds were taken by using the KBr disc method on a Bruker ALPHA-T FT-IR spectrometer, the values are expressed in cm -1 . The 1 H & 13 C NMR spectra of the compounds were recorded using DMSO-d 6 on Bruker Avance 400 MHz and 100 MHz NMR spectrometers. The elemental analysis experiments were conducted using Carlo-Erba elemental analyzer.…”

Section: Methodsmentioning

confidence: 99%

“…As a result, mycolic acid methyl transferases (MAMTs) may be promising targets for the discovery and development of novel, selective anti-TB drugs. Recently, a structure-based drug design study carried out in our research lab led to the identification of 3-(2-morpholinoacetamido)-N-(3,4-dihydro-4-oxoquinazolin-7-yl)-benzamide and its intermediates as inhibitors of the MmaA1 protein [13]. The intermediate compounds 3-(2-chloroacetamido) benzoic acid or 3-(N-substituted glycinamido) benzoic acid have shown an MIC of 25 µg/mL against M. tuberculosis H37Rv, in contrast to the parent molecule's activity of 100 µg/mL.…”

Section: Introductionmentioning

confidence: 99%

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Docking Studies, Synthesis, SAR and Anti-TB Activity of Glycinamido Analogues

Vaidehi,

Veeravarapu,

Muthyala

2024

ajc

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Mycolic acid is a crucial component of the Mycobacterium tuberculosis cell wall and mycolic acid methyltransferases (MAMTs) are essential for mycolic acids to mature. In the present study, an inhouse library of 330 ligands was designed taking glycinamido moiety as scaffold. Virtual screening was carried out with this library of compounds against MmaA1 as the target protein. About 55 hits were identified through docking, ADMET studies and these molecules were synthesized by the Schotten-Baumann reaction followed by a nucleophilic substitution reaction. All the compounds were subjected to in vitro anti-Tb screening by microplate alamar blue assay (MABA). The Mdb1, Mdb4 & Meb1 exhibited excellent activity against M. tuberculosis H37Rv bacilli strain with an MIC of 1.56 µg/mL. The SAR studies shows that the aryl ring attached directly to the nitrogen atom as present in 2(-N-substituted glycinamido) derivatives is essential for the compound to exhibit potent anti-TB activity.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Docking Studies, Synthesis, SAR and Anti-TB Activity of Glycinamido Analogues

Vaidehi,

Veeravarapu,

Muthyala

2024

ajc

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“…The selected homologous template protein is used to evaluate the target protein 3D structure. Several in silico methodologies are reported on structure‐based design methods with good results 19 …”

Section: Methodsmentioning

confidence: 99%

“…Several in silico methodologies are reported on structure-based design methods with good results. 19…”

Section: Homology Modeling Of Pimamentioning

confidence: 99%

Identification of novel scaffolds to inhibit Mycobacterium tuberculosis PimA protein—A computational approach

Damera

Kondaparthi

Bingi

et al. 2023

J of Cellular Biochemistry

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Phosphatidyl‐myo‐inositol mannosyltransferase (Pim) is a subset of the Glycosyl transferase type family that has been synthesized from 1D‐myo‐inositol and GDP‐α‐d‐mannose reaction in the presence of PimA protein as a catalyst, which PimA protein is identified as a high‐confidence therapeutic target. In‐silico technique such as homology modeling is the most efficient approach for discovering a new framework to study the modulations of protein function. Using In‐silico approaches, therapeutic compounds with high affinity, specificity, activity, low harmfulness, and no side effects can be found. Applying the Modeller software and molecular dynamics simulations, a stable three‐dimensional (3D) model of the PimA protein is produced. The modeled PimA protein consists of 20 helices and 27 twists in its 3D structure. Lead compounds that inhibit the PimA protein are found by applying the Schrodinger suite and the PyRx virtual screening tools. The amino acid residues PRO14 and ASP253 are identified as active residues involved in binding with the ligands. High‐potential lead compounds are discovered as ligand scaffolds against PimA protein with satisfactory ADME capabilities.

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“…Tetrahydropyrazo (1,5-a)pyrimidine-3-carboxamides (THPPs) have recently been shown to target EchA6, a catalytically inactive enoyl-CoA hydratase required for shuttling fatty acyl-CoA esters into FAS-II for MA biosynthesis ( Cox et al., 2016 ). MmaA1 is a target of the compound 3-(2-morpholinoacetamido)- N -(1,4-dihydro-4-oxoquinazolin-6-yl)benzamide ( Veeravarapu et al., 2020 ). Benzofurans, coumestans, thiophenes, β-lactones target Pks13 ( Wilson et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets

Shaku

Ealand

Kana

2020

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis ( Mtb ), the causative agent of tuberculosis (TB), remains the leading cause of death from an infectious bacterium and is responsible for 1.8 million deaths annually. The emergence of drug resistance, together with the need for a shorter more effective regimen, has prompted the drive to identify novel therapeutics with the bacterial cell surface emerging as a tractable area for drug development. Mtb assembles a unique, waxy, and complex cell envelope comprised of the mycolyl-arabinogalactan-peptidoglycan complex and an outer capsule like layer, which are collectively essential for growth and pathogenicity while serving as an inherent barrier against antibiotics. A detailed understanding of the biosynthetic pathways required to assemble the polymers that comprise the cell surface will enable the identification of novel drug targets as these structures provide a diversity of biochemical reactions that can be targeted. Herein, we provide an overview of recently described mycobacterial cell wall targeting compounds, novel drug combinations and their modes of action. We anticipate that this summary will enable prioritization of the best pathways to target and triage of the most promising molecules to progress for clinical assessment.

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Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents

Cited by 14 publications

References 48 publications

Docking Studies, Synthesis, SAR and Anti-TB Activity of Glycinamido Analogues

Docking Studies, Synthesis, SAR and Anti-TB Activity of Glycinamido Analogues

Identification of novel scaffolds to inhibit Mycobacterium tuberculosis PimA protein—A computational approach

Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets

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