Robust design of some selective matrix metalloproteinase-2 inhibitors over matrix metalloproteinase-9 through in silico/fragment-based lead identification and de novo lead modification: Syntheses and biological assays

Adhikari, Nilanjan; Halder, Amit Kumar; Mallick, Sumana; Saha, Achintya; Saha, Kishna D.; Jha, Tarun

doi:10.1016/j.bmc.2016.07.023

Cited by 48 publications

(24 citation statements)

References 77 publications

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“…Moreover, the association of biphenyl function with the ring aromatic features of pharmacophore mapping suggests that the ring aromaticity may play important roles in higher MMP‐2 inhibition. The structure‐based contour map of the most potent compound (Cpd 48 ) also justify these observations (Figure ).…”

Section: Resultssupporting

confidence: 52%

“…Therefore, designing potent and selective MMP‐2 inhibitors is still in demand to combat the dreaded disease cancer. Though several alignment‐based 3D‐QSAR studies were performed earlier on different MMP‐2 inhibitors, none of these highlighted any robust alignment dependent QSARs . Zheng et al .…”

Section: Introductionmentioning

confidence: 99%

“…This model also failed to pass the acceptable model criteria regarding internal validation ( Q 2 =0.469 < 0.50) whereas, the R 2 Pred value of this model was quite higher (0.834). In the earlier study, 3D‐QSAR CoMFA and CoMSIA models were generated on 214 diverse MMP‐2 inhibitors depending on the alignment of these molecules derived from the best Hypogen‐pharmacophore model. None of these 3D‐QSAR models were developed comprising multiple types of alignment methods.…”

Section: Introductionmentioning

confidence: 99%

“…In the earlier study, 3D‐QSAR CoMFA and CoMSIA models were generated on 214 diverse MMP‐2 inhibitors depending on the alignment of these molecules derived from the best Hypogen‐pharmacophore model. None of these 3D‐QSAR models were developed comprising multiple types of alignment methods. In the current study, a variety of comprehensive alignment‐dependent (namely pharmacophore‐based, docking‐based and Open3DALIGN‐based alignment) 3D‐QSAR techniques have been performed to explore the structure‐property relationship of a series of glutamate‐based MMP‐2 inhibitors synthesized in the laboratory, for higher inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

“…None of these 3D‐QSAR models were developed comprising multiple types of alignment methods. In the current study, a variety of comprehensive alignment‐dependent (namely pharmacophore‐based, docking‐based and Open3DALIGN‐based alignment) 3D‐QSAR techniques have been performed to explore the structure‐property relationship of a series of glutamate‐based MMP‐2 inhibitors synthesized in the laboratory, for higher inhibitory activity. The MMP‐2 inhibitory activity (IC 50 in nM) of these compounds was transformed into the corresponding negative logarithmic scale [pIC 50 =log10 9 /IC 50 ] and was utilized for the development of 3D‐QSAR models.…”

Section: Introductionmentioning

confidence: 99%

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Understanding Chemico‐Biological Interactions of Glutamate MMP‐2 Inhibitors through Rigorous Alignment‐Dependent 3D‐QSAR Analyses

et al. 2017

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The current study involves different alignment techniques (pharmacophore‐based, docking‐based and Open3DALIGN‐based) extensively at the first time to build three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on some potential glutamate‐based in house MMP‐2 inhibitors. The docking‐based alignment method yields the best 3D‐QSAR models though other alignment‐based methods also provide statistically significant and validated models. 3D‐QSAR models are correlated with molecular docking study and pharmacophore mapping. Biphenyl moiety of glutamines enters into the S1′ pocket and involves π‐π interactions with Tyr142 and His120, while none of the phenylacetyl/naphthylacetyl isoglutamines interacts with Tyr142. 3D‐QSAR models also suggest the importance of hydrophobicity and steric features of biphenyl function required for higher MMP‐2 inhibition. The sulfonyl oxygen may form potential hydrogen bonding interaction with Leu83 and Ala84 of S1' pocket. This study clearly points out that biphenylsulfonyl glutamines are favorable than phenylacetyl/naphthylacetyl isoglutamines for imparting higher MMP‐2 inhibition.

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Section: Resultssupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Understanding Chemico‐Biological Interactions of Glutamate MMP‐2 Inhibitors through Rigorous Alignment‐Dependent 3D‐QSAR Analyses

et al. 2017

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Automated De Novo Drug Design: Are We Nearly There Yet?

Schneider

Clark

2019

Angewandte Chemie

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Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.

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