TY - JOUR
T1 - Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb
AU - Kwofie, Samuel K.
AU - Hanson, George
AU - Sasu, Henrietta
AU - Enninful, Kweku S.
AU - Mensah, Francis A.
AU - Nortey, Richmond T.
AU - Yeboah, Omane P.
AU - Agoni, Clement
AU - Wilson, Michael D.
N1 - Publisher Copyright:
© 2022 Wiley-VHCA AG, Zurich, Switzerland.
PY - 2022/9
Y1 - 2022/9
N2 - Mycobacterial membrane proteins Large (MmpLs), which belong to the resistance, nodulation, and division (RND) protein superfamily, play critical roles in transporting polymers, lipids, and immunomodulators. MmpLs have become one of the important therapeutic drug targets to emerge in recent times. In this study, two homology modelling techniques, Modeller and SWISS-MODEL, were used in modelling the three-dimensional protein structure of the MmpL3 of Mycobacterium tuberculosis using that of M. smegmatis as template. MmpL3 inhibitors, namely BM212, NITD304, SPIRO, and NITD349, in addition to the co-crystalized ligands AU1235, ICA38, SQ109 and rimonabant, were screened against the modelled structure and the Mmpl3 of M. smegmatis using molecular docking techniques. Protein-ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.
AB - Mycobacterial membrane proteins Large (MmpLs), which belong to the resistance, nodulation, and division (RND) protein superfamily, play critical roles in transporting polymers, lipids, and immunomodulators. MmpLs have become one of the important therapeutic drug targets to emerge in recent times. In this study, two homology modelling techniques, Modeller and SWISS-MODEL, were used in modelling the three-dimensional protein structure of the MmpL3 of Mycobacterium tuberculosis using that of M. smegmatis as template. MmpL3 inhibitors, namely BM212, NITD304, SPIRO, and NITD349, in addition to the co-crystalized ligands AU1235, ICA38, SQ109 and rimonabant, were screened against the modelled structure and the Mmpl3 of M. smegmatis using molecular docking techniques. Protein-ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.
KW - Mycobacterium Smegmatis
KW - Mycobacterium tuberculosis
KW - molecular docking
KW - molecular dynamics simulations
KW - mycobacterial membrane proteins large (MmpL3)
UR - http://www.scopus.com/inward/record.url?scp=85137234691&partnerID=8YFLogxK
U2 - 10.1002/cbdv.202200160
DO - 10.1002/cbdv.202200160
M3 - Article
C2 - 35969844
AN - SCOPUS:85137234691
SN - 1612-1872
VL - 19
JO - Chemistry and Biodiversity
JF - Chemistry and Biodiversity
IS - 9
M1 - e202200160
ER -
