cells. FtsZ is a prokaryotic homologue to the eukaryotic protein tubulin. It contains
a GGGTGTG motif like in tubulin for guanine binding in FtsZ and also shows
GTPase activity [106]. So, blocking of FtsZ leads to cell division arrest leading to
bacterial death [107]. Das et al. recently identified phytochemicals as FtsZ inhibitor
through molecular docking-based VS; however, no experimental validation was
performed by that group [108].
Caseinolytic peptidase P (ClpP) is another important molecular target in Mtb.
ClpP acts in association with ATPases to perform energy-dependant degradation of
damaged proteins within the cell. Mtb encodes two ClpP homologues, ClpP1 and
ClpP2, and forms a mixed protein called ClpP1P2 [109]. It was experimentally validated that both ClpP1 and ClpP2 are required for the protein degradation and
depletion of either of the protein results in bacterial death [110]. A novel natural
product, lassomycin, is found to inhibit ClpP [111]. Schmitz et al. solved the X-ray
structure of ClpP1P2 and elucidated the molecular mechanism of association with
ATPases [112]. This will aid in designing of novel and more potent inhibitors of ClpP
protein. Mtb produces 20S proteasome, which is essential for the survival of the
bacteria within the host and helps in defending the bacilli against nitrosative stress
[109, 113]. Gandotra et al. demonstrated that prcBA genes encoding mycobacterial
proteasome are essential for the Mtb survival in chronic phase of infection in mice
[114]. Hence, 20S proteasome serves as an important mycobacterial target for
inhibitor design.
The enzymes involved in menaquinone (Vitamin K2) synthesis, menA, menB,
menC, menD, menE, menF, and ubiE (menG), serve as an important druggable
target for anti-mycobacterial therapy [115, 116]. It has been proved that
Menaquinone synthesis is important for maintaining the mycobacterial viability
during the exponential growth phase and recovery from non-replicating persistence
and also involved in electron transfer pathways.
3 Structure-Based Anti-TB Drug Design Approach
and Its Molecular Mechanism of Action
Structure-based inhibitor design for the past two decades became significant due to
the theoretical and experimental technological advancements which include: protein
modeling, ab initio modeling, homology modeling, protein folding dynamics,
molecular docking, pharmacophore modeling, virtual screening, quantitative
structure activity relationship (QSAR), structural biology, nuclear magnetic resonance (NMR) studies toward the preclinical drug discovery program. 3D structural
data present in the protein data bank (PDB) and other pharmaceutical databases
contain many millions of datasets which fit into the big data domain. This vast
amount of data can provide information about the key molecular mechanism of
action at the atomic level. Nowadays, structure- and ligand-based drug design has
also become a fundamental strategy in both lead generation and lead optimization.
Impact of Target-Based Drug Design in Anti-bacterial …
323
a GGGTGTG motif like in tubulin for guanine binding in FtsZ and also shows
GTPase activity [106]. So, blocking of FtsZ leads to cell division arrest leading to
bacterial death [107]. Das et al. recently identified phytochemicals as FtsZ inhibitor
through molecular docking-based VS; however, no experimental validation was
performed by that group [108].
Caseinolytic peptidase P (ClpP) is another important molecular target in Mtb.
ClpP acts in association with ATPases to perform energy-dependant degradation of
damaged proteins within the cell. Mtb encodes two ClpP homologues, ClpP1 and
ClpP2, and forms a mixed protein called ClpP1P2 [109]. It was experimentally validated that both ClpP1 and ClpP2 are required for the protein degradation and
depletion of either of the protein results in bacterial death [110]. A novel natural
product, lassomycin, is found to inhibit ClpP [111]. Schmitz et al. solved the X-ray
structure of ClpP1P2 and elucidated the molecular mechanism of association with
ATPases [112]. This will aid in designing of novel and more potent inhibitors of ClpP
protein. Mtb produces 20S proteasome, which is essential for the survival of the
bacteria within the host and helps in defending the bacilli against nitrosative stress
[109, 113]. Gandotra et al. demonstrated that prcBA genes encoding mycobacterial
proteasome are essential for the Mtb survival in chronic phase of infection in mice
[114]. Hence, 20S proteasome serves as an important mycobacterial target for
inhibitor design.
The enzymes involved in menaquinone (Vitamin K2) synthesis, menA, menB,
menC, menD, menE, menF, and ubiE (menG), serve as an important druggable
target for anti-mycobacterial therapy [115, 116]. It has been proved that
Menaquinone synthesis is important for maintaining the mycobacterial viability
during the exponential growth phase and recovery from non-replicating persistence
and also involved in electron transfer pathways.
3 Structure-Based Anti-TB Drug Design Approach
and Its Molecular Mechanism of Action
Structure-based inhibitor design for the past two decades became significant due to
the theoretical and experimental technological advancements which include: protein
modeling, ab initio modeling, homology modeling, protein folding dynamics,
molecular docking, pharmacophore modeling, virtual screening, quantitative
structure activity relationship (QSAR), structural biology, nuclear magnetic resonance (NMR) studies toward the preclinical drug discovery program. 3D structural
data present in the protein data bank (PDB) and other pharmaceutical databases
contain many millions of datasets which fit into the big data domain. This vast
amount of data can provide information about the key molecular mechanism of
action at the atomic level. Nowadays, structure- and ligand-based drug design has
also become a fundamental strategy in both lead generation and lead optimization.
Impact of Target-Based Drug Design in Anti-bacterial …
323