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An Integrated Computational and Experimental Approach to Gaining Selectivity for MMP-2 within the Gelatinase Subfamily

Authors

  • Benjamin Fabre,

    1. Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)
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  • Kamila Filipiak,

    1. Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)
    2. Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynow 1i, 20-718 Lublin (Poland)
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  • Dr. Natalia Díaz,

    1. Departamento de Química Física y Analítica, Julián Clavería 8, 33006 Oviedo, Asturias (Spain)
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  • Dr. José María Zapico,

    1. Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)
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  • Dr. Dimas Suárez,

    1. Departamento de Química Física y Analítica, Julián Clavería 8, 33006 Oviedo, Asturias (Spain)
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  • Prof. Ana Ramos,

    Corresponding author
    1. Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)
    • Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)

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  • Prof. Beatriz de Pascual-Teresa

    Corresponding author
    1. Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)
    • Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, Ctra. Boadilla del Monte Km 5,3. 28668 Madrid (Spain)

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Abstract

Looking for water-soluble inhibitors of matrix metalloproteinase-2 (MMP-2 or gelatinase A), we have previously reported compound 1, a potent MMP-2 inhibitor with a promising selectivity over the structurally homologous MMP-9 (gelatinase B). Here we report the results of Molecular Dynamics (MD) simulations for both gelatinases (MMP-2 and MMP-9), and for the corresponding MMP/1 complexes, in an attempt to shed light on the observed selectivity between the two enzymes. These studies indicated a higher plasticity of MMP-2 at the S1′ pocket and suggested an induced-fit effect at the “back door” of this pocket. On the basis of these observations, we designed 11 ad to aid further discrimination between MMP-2 and MMP-9. Those compounds displayed notably lower inhibitory activities against MMP-9; in particular, 11 b proved to be over 100 times more active against MMP-2 than against MMP-9. MD simulations of the MMP/11 b complexes and thermodynamic integration calculations provided structural insight and relative binding energies consistent with the experimentally observed activity data. These findings demonstrate that structural differences in the S1′ pocket bottom permit an improvement in selectivity in the inhibition of MMP-2 over that of MMP-9; this is of great relevance for future structure-based drug design because MMP-2 is a validated target for cancer therapy, whereas MMP-9 plays both detrimental and protective roles in cancer. This study also supports the need to consider the dynamics of the S1′ pocket in order to achieve selectivity in the inhibition of MMPs.

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