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

Molecular Diversity
Hymavathi VeeravarapuMurali Krishna Kumar Muthyala

Abstract

Tuberculosis is one of the leading causes of death across the world. The treatment regimens for tuberculosis are well established, but still the control of the disease faces many challenges such as lengthy treatment protocols, drug resistance and toxicity. In the present work, mycolic acid methyl transferase (MmaA1), a protein involved in the maturation of mycolic acids in the biochemical pathway of the Mycobacterium, was studied for novel drug discovery. The homology model of the MmaA1 protein was built and validated by using computational techniques. The MmaA1 protein has 286 amino acid residues consisting of 10 α-helices and 7 β-sheets. The active site of the MmaA1 protein was identified using CASTp, SiteMap and PatchDock. Virtual screening studies were performed with two small molecule ligand databases: Asinex synergy and Diverse_Elite_Gold_Platinum databases having a total of 43,446 molecules and generated 1,30,814 conformers against the predicted and validated active site of the MmaA1 protein. Binding analysis showed that the residues ASP 19, PHE 22, TRP 30, TYR 32, TRP 74 and ALA 77 of MmaA1 protein have consistent interactions with the ligands. The hit ligands were further filtered by in silico ADME properties to elimin...Continue Reading

References

Oct 5, 1990·Journal of Molecular Biology·S F AltschulD J Lipman
Apr 1, 1994·Protein Science : a Publication of the Protein Society·K Y Zhang, D Eisenberg
May 26, 1997·Journal of Immunological Methods·G R NakayamaZ Parandoosh
Nov 26, 1998·Progress in Lipid Research·C E BarryY Yuan
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Mar 29, 2001·Journal of Pharmacological and Toxicological Methods·S EkinsJ H Wikel
Aug 10, 2002·Progress in Lipid Research·Cécile AsselineauMarie-Antoinette Lanéelle
Nov 9, 2002·Bioinformatics·S S SheikK Sekar
Jun 26, 2003·Nucleic Acids Research·Elisabeth GasteigerAmos Bairoch
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Jul 13, 2004·Diagnostic Microbiology and Infectious Disease·J Daisy Vanitha, C N Paramasivan
Nov 3, 2004·Nature Reviews. Drug Discovery·Douglas B KitchenJürgen Bajorath
Dec 17, 2004·Nature·Brian K Shoichet
Jan 18, 2005·Clinical Microbiology Reviews·Kuni TakayamaGurdyal S Besra
Jun 28, 2005·Nucleic Acids Research·Dina Schneidman-DuhovnyHaim J Wolfson
Jun 28, 2005·Nucleic Acids Research·Roman A LaskowskiJanet M Thornton
Mar 27, 2007·Chemical Biology & Drug Design·Tom Halgren
May 23, 2007·Nucleic Acids Research·Markus Wiederstein, Manfred J Sippl
May 9, 2008·Nucleic Acids Research·Christian ColeGeoffrey J Barton
Jan 27, 2009·Chemical Society Reviews·Eric Valeur, Mark Bradley
Feb 3, 2009·Nature Chemical Biology·Pooja AroraRajesh S Gokhale
Sep 1, 2009·Toxicology and Applied Pharmacology·Luis G Valerio
Jan 8, 2010·Protein Science : a Publication of the Protein Society·Christine E CadeReza A Ghiladi
Mar 17, 2012·European Journal of Medicinal Chemistry·Baptiste VillemagneNicolas Willand
Jan 4, 2013·The New England Journal of Medicine·Salmaan Keshavjee, Paul E Farmer
Jan 4, 2013·The New England Journal of Medicine·Giovanni SotgiuGiovanni B Migliori
Feb 9, 2013·Nature Biotechnology·Randy Osborne
Jan 1, 2014·Chemistry & Biology·Hedia MarrakchiMamadou Daffé
May 6, 2014·Journal of Molecular Graphics & Modelling·Francisco CarrascozaRadu Silaghi-Dumitrescu
Sep 10, 2014·Current Protocols in Bioinformatics·Benjamin Webb, Andrej Sali
Jul 30, 2015·Anais Da Academia Brasileira De Ciências·Gabriel F RioAngelo C Pinto
Jan 30, 2018·Biotechnology and Applied Biochemistry·Rajender VadijaUma Vuruputuri
Mar 20, 2018·European Journal of Medicinal Chemistry·André CampaniçoFrancisca Lopes
Apr 10, 2018·Journal of Molecular Recognition : JMR·Ramakrishna DumpatiUma Vuruputuri

❮ Previous
Next ❯

Citations

Dec 8, 2020·Frontiers in Cellular and Infection Microbiology·Moagi ShakuBavesh D Kana

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR
Assay
X-ray

Software Mentioned

SciFinder
PyMOL
ClustalW
HTVS
JPred3
TrEMBL )
Accelrys Discovery Studio
PatchDock
ProFunc
Server Expert Protein Analysis System ( Expasy SWISS - PROT /

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.