Computer-Assisted Design of Hydroxamic Acid Derivatives Inhibitors of M1 Metallo Aminopeptidase of Plasmodium falciparum with Favorable Pharmacokinetic Profile
Journal of Pharmaceutical Research International, Volume 34, Issue 60,
Page 21-44
DOI:
10.9734/jpri/2022/v34i607271
Abstract
We virtually design here new subnanomolar range antimalarial, inhibitors of plasmodium falciparum M1 Aminopeptidase (PfA-M1), by means of structure-based molecular design. We developed the complexation QSAR models from Hydroxamic Acid derivatives (AHO). A linear correlation was established between the computed Gibbs free energies of binding (GFE: ∆∆Gcom) and observed enzyme inhibition constants (Kiexp) for each training set pKiexp = −0.063×∆∆Gcom+ 8.003, R2 = 0.92. The predictive power of the QSAR model was validated with 3D-QSAR pharmacophore generation (PH4): pKiexp = 1.0289×pKipred − 0.155, R2 = 0.90. We then conducted a study on catalytic residues to exploit the different interactions (enzyme: inhibitor). Structural information from the models guided us in designing of a virtual combinatorial library (VCL) of more than 44 thousands AHOs. The PH4 screening retained 51 new and potent AHOs with predicted inhibitory potencies pKipre up to 13 times lower than that of AHO1 (pKiexp = 700 nM). Combining molecular modeling and PH4 in silico screening of the VCL resulted in the proposed novel potent antimalarial agent candidates with favorable pharmacokinetic profiles.
Keywords:
- Drug design
- QSAR model
- pharmacophore model
- complexation model
- molecular modeling
- ADMET
How to Cite
Adama, N., N’Guessan, H., Dali, B. and Megnassan, E. (2022) “Computer-Assisted Design of Hydroxamic Acid Derivatives Inhibitors of M1 Metallo Aminopeptidase of Plasmodium falciparum with Favorable Pharmacokinetic Profile”, Journal of Pharmaceutical Research International, 34(60), pp. 21-44. doi: 10.9734/jpri/2022/v34i607271.
References
World malaria report 2021. Geneva, World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO.
Available:https://apps.who.int/iris/handle/10665/350147
World malaria report 2019. Geneva: World Health Organization; 2019. Licence:CCBY-NC-SA 3.0 IGO.
World Health Organization (WHO). Practical guide for treatment, severe malaria. 3rd ed. 2015;83.
Uwimana A, Legrand E, Stokes BH, Ndikumana JM, Warsame M, Umulisa N et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med. 2020; 6:1602-8.
Zhu L, van der Pluijm RW, Kucharski M, Nayak S, Tripathi J, White NJ et al. Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response. Commun Biol. 2022;5(1):274.
Ragheb D, Dalal S, Bompiani KM, Ray WK, Klemba M. Distribution and biochemical properties of an M1-family aminopeptidase in Plasmodium falciparum indicate a role in vacuolar hemoglobin catabolism. J Biol Chem. 2011;286(31):27255-65.
Dalal S, Klemba M. Roles for two aminopeptidases in vacuolar hemoglobin catabolism in Plasmodium falciparum. J Biol Chem. 2007;282(49):35978-87.
McGowan S. Working in concert: the metalloaminopeptidases from Plasmodium falciparum. Curr Opin Struct Biol. 2013; 23(6):828-35.
Mucha A, Drag M, Dalton JP, Kafarski P. Metallo-aminopeptidase inhibitors. Biochimie. 2010;92(11):1509-29.
Cunningham E, Drag M, Kafarski P, Bell A. Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors. Antimicrob Agents Chemother. 2008;52(9):3221-8.
McGowan S, Oellig CA, Birru WA, Caradoc-Davies TT, Stack CM, Lowther J et al. Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases. Proc Natl Acad Sci U S A. 2010;107(6):2449-54.
Kannan Sivaraman K, Paiardini A, Sieńczyk M, Ruggeri C, Oellig CA, Dalton JP et al. Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum. J Med Chem. 2013;56(12): 5213-7.
Verma R. Hydroxamic acids as matrix metalloproteinase inhibitors in: Gupta SP (ed) matrix metalloproteinase inhibitors: specificity of binding and structure-activity relationships. Springer Basel Agric. 2012;103:137-76.
Velmourougane G, Harbut MB, Dalal S. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. J Med Chem. 2011;54:1655-66.
McGowan S, Porter CJ, Lowther J, Stack CM, Golding SJ, Skinner-Adams TS et al. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc Natl Acad Sci U S A. 2009;106(8):2537-42.
Kannan Sivaraman K, Paiardini A, Sieńczyk M, Ruggeri C, Oellig CA, Dalton JP et al. Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum. J Med Chem. 2013;56(12) :5213-7.
Patrick GL. Antimalarial agents design and mechanism of action. Amsterdam, Netherlands: Elsevier; 2020.
Deprez-Poulain R, Flipo M, Piveteau C, Leroux F, Dassonneville S, Florent I et al. Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors. J Med Chem. 2012;55(24):10909-17.
Shailesh Mistry N, Drinkwater N, Ruggeri C, Sivaraman KK, Logonathan S, Fletcher S et al. Two-prongead attack: dual inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a new series of hydroxamic acid-Based inhibitors. J Med Chem. 2014;57:9168- 83.
Drinkwater N, Vinh NB, Mistry SN, Bamert RS, Ruggeri C, Holleran JP et al. Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. Eur J Med Chem. 2016;110:43-64.
Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM et al. Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases. J Med Chem. 2019; 62(2):622-40.
Kurogi Y, Güner OF. Pharmacophore modeling and three-dimensional database searching for drug design using catalyst. Curr Med Chem. 2001;8(9):1035-55.
Insight-II. Insight-II and DISCover molecular modeling and simulation package, Version. San Diego: Accelrys, Incorp; 2005.
Discovery Studio Molecular Modeling and Simulation Program. v2.5. San Diego: Accelrys, Incorp; 2009.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H et al. The protein data bank. Nucleic Acids Res. 2000;28(1):235-42.
Allangba K, Keita M, Kre N’Guessan R, Megnassan E, V. Frecer et S. Miertus, Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone chalcone and isatin-chalcone inhibitors probing the lactone chalcone and isatin-chalcone inhibitors probing the S2 active site pocket. J Enz Inhib Med Chem. 2018;34:547-61.
Chaquin P. Manual of theoretical chemistry application to structure and reactivity in molecular chemistry. p. 190.
Maple JR, Hwang M-J, Stockfisch TP, Dinur U, Waldman M, Ewig CS et al. Derivation of class II force fields. I. Methodology and quantum force field for the alkyl functional group and alkane molecules. J Comput Chem. 1994;15(2): 162-82.
Dugas H. Basic principles in molecular modeling, theoretical and practical aspects. 4th ed, University of Montreal Bookstore; 1996.
Bartol J, Comba P, Melter M, Zimmer M. Conformational searching of transition metal compounds. J Comput Chem. 1999;20(14):1549-58.
Kouassi AF, Kone M, Keita M, Esmel A, Megnassan E, N’Guessan YT et al. Computer-aided design of orally bioavailable pyrrolidine carboxamide inhibitors of enoyl-acyl Carrier Protein reductase of Mycobacterium tuberculosis with favorable pharmacokinetic profiles. Int J Mol Sci. 2015;16(12):29744-71.
Gilson MK, Honig B. The inclusion of electrostatic hydration energies in molecular mechanics calculations. J Comput Aid Mol Des. 1991;5(1):5-20.
Rocchia W, Sridharan S, Nicholls A, Alexov E, Chiabrera A, Honig B. Rapid grid-based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: applications to the molecular systems and geometric objects. J Comput Chem. 2002; 23(1):128-37.
Megnassan E, Keita M, Bieri C, Esmel A, Frecer V, Miertus S. Design of novel dihydroxynaphthoic acid inhibitors of Plasmodium falciparum lactate dehydrogenase. Med Chem. 2012;8(5): 970-84.
Frecer V, Miertuš S. Polarizable continuum model of solvation for biopolymers. Int J Quantum Chem. 1992;42(5):1449-68.
Böttcher CJF. Theory of electric polarization. Amsterdam, The Netherlands: Elsevier; 1973.
Miertuš S, Scrocco E, Tomasi J. Electrostatic interaction of a solute with a continuum. A direct utilizaion of ab initio molecular potentials for the prevision of solvent effects. Chem Phys. 1981;55(1): 117-29.
Frecer V, Miertuš S. Polarizable continuum model of solvation for biopolymers. Int J Quantum Chem. 1992;42(5):1449-68.
Krovat EM, Frühwirth KH, Langer T. Pharmacophore identification, in silico screening, and virtual library design for inhibitors of the human factor Xa. J Chem Inf Model. 2005;45(1):146-59.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26.
Daily JP. Antimalarial drug therapy: the role of parasite biology and drug resistance. J Clin Pharmacol. 2006;46(12): 1487-97.
Stec J, Vilchèze C, Lun S, Perryman A, Wang X, J. Freundlich et A. Kozikowski, Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. J Med Chem. 2014;9:2528-37.
Jorgensen WL, Duffy EM. Prediction of drug solubility from Monte Carlo simulations. Bioorg Med Chem Lett. 2000;10(11):1155-8.
Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Deliv Rev. 2002;54(3):355-66.
Available:https://apps.who.int/iris/handle/10665/350147
World malaria report 2019. Geneva: World Health Organization; 2019. Licence:CCBY-NC-SA 3.0 IGO.
World Health Organization (WHO). Practical guide for treatment, severe malaria. 3rd ed. 2015;83.
Uwimana A, Legrand E, Stokes BH, Ndikumana JM, Warsame M, Umulisa N et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med. 2020; 6:1602-8.
Zhu L, van der Pluijm RW, Kucharski M, Nayak S, Tripathi J, White NJ et al. Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response. Commun Biol. 2022;5(1):274.
Ragheb D, Dalal S, Bompiani KM, Ray WK, Klemba M. Distribution and biochemical properties of an M1-family aminopeptidase in Plasmodium falciparum indicate a role in vacuolar hemoglobin catabolism. J Biol Chem. 2011;286(31):27255-65.
Dalal S, Klemba M. Roles for two aminopeptidases in vacuolar hemoglobin catabolism in Plasmodium falciparum. J Biol Chem. 2007;282(49):35978-87.
McGowan S. Working in concert: the metalloaminopeptidases from Plasmodium falciparum. Curr Opin Struct Biol. 2013; 23(6):828-35.
Mucha A, Drag M, Dalton JP, Kafarski P. Metallo-aminopeptidase inhibitors. Biochimie. 2010;92(11):1509-29.
Cunningham E, Drag M, Kafarski P, Bell A. Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors. Antimicrob Agents Chemother. 2008;52(9):3221-8.
McGowan S, Oellig CA, Birru WA, Caradoc-Davies TT, Stack CM, Lowther J et al. Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases. Proc Natl Acad Sci U S A. 2010;107(6):2449-54.
Kannan Sivaraman K, Paiardini A, Sieńczyk M, Ruggeri C, Oellig CA, Dalton JP et al. Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum. J Med Chem. 2013;56(12): 5213-7.
Verma R. Hydroxamic acids as matrix metalloproteinase inhibitors in: Gupta SP (ed) matrix metalloproteinase inhibitors: specificity of binding and structure-activity relationships. Springer Basel Agric. 2012;103:137-76.
Velmourougane G, Harbut MB, Dalal S. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. J Med Chem. 2011;54:1655-66.
McGowan S, Porter CJ, Lowther J, Stack CM, Golding SJ, Skinner-Adams TS et al. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc Natl Acad Sci U S A. 2009;106(8):2537-42.
Kannan Sivaraman K, Paiardini A, Sieńczyk M, Ruggeri C, Oellig CA, Dalton JP et al. Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum. J Med Chem. 2013;56(12) :5213-7.
Patrick GL. Antimalarial agents design and mechanism of action. Amsterdam, Netherlands: Elsevier; 2020.
Deprez-Poulain R, Flipo M, Piveteau C, Leroux F, Dassonneville S, Florent I et al. Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors. J Med Chem. 2012;55(24):10909-17.
Shailesh Mistry N, Drinkwater N, Ruggeri C, Sivaraman KK, Logonathan S, Fletcher S et al. Two-prongead attack: dual inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a new series of hydroxamic acid-Based inhibitors. J Med Chem. 2014;57:9168- 83.
Drinkwater N, Vinh NB, Mistry SN, Bamert RS, Ruggeri C, Holleran JP et al. Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. Eur J Med Chem. 2016;110:43-64.
Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM et al. Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases. J Med Chem. 2019; 62(2):622-40.
Kurogi Y, Güner OF. Pharmacophore modeling and three-dimensional database searching for drug design using catalyst. Curr Med Chem. 2001;8(9):1035-55.
Insight-II. Insight-II and DISCover molecular modeling and simulation package, Version. San Diego: Accelrys, Incorp; 2005.
Discovery Studio Molecular Modeling and Simulation Program. v2.5. San Diego: Accelrys, Incorp; 2009.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H et al. The protein data bank. Nucleic Acids Res. 2000;28(1):235-42.
Allangba K, Keita M, Kre N’Guessan R, Megnassan E, V. Frecer et S. Miertus, Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone chalcone and isatin-chalcone inhibitors probing the lactone chalcone and isatin-chalcone inhibitors probing the S2 active site pocket. J Enz Inhib Med Chem. 2018;34:547-61.
Chaquin P. Manual of theoretical chemistry application to structure and reactivity in molecular chemistry. p. 190.
Maple JR, Hwang M-J, Stockfisch TP, Dinur U, Waldman M, Ewig CS et al. Derivation of class II force fields. I. Methodology and quantum force field for the alkyl functional group and alkane molecules. J Comput Chem. 1994;15(2): 162-82.
Dugas H. Basic principles in molecular modeling, theoretical and practical aspects. 4th ed, University of Montreal Bookstore; 1996.
Bartol J, Comba P, Melter M, Zimmer M. Conformational searching of transition metal compounds. J Comput Chem. 1999;20(14):1549-58.
Kouassi AF, Kone M, Keita M, Esmel A, Megnassan E, N’Guessan YT et al. Computer-aided design of orally bioavailable pyrrolidine carboxamide inhibitors of enoyl-acyl Carrier Protein reductase of Mycobacterium tuberculosis with favorable pharmacokinetic profiles. Int J Mol Sci. 2015;16(12):29744-71.
Gilson MK, Honig B. The inclusion of electrostatic hydration energies in molecular mechanics calculations. J Comput Aid Mol Des. 1991;5(1):5-20.
Rocchia W, Sridharan S, Nicholls A, Alexov E, Chiabrera A, Honig B. Rapid grid-based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: applications to the molecular systems and geometric objects. J Comput Chem. 2002; 23(1):128-37.
Megnassan E, Keita M, Bieri C, Esmel A, Frecer V, Miertus S. Design of novel dihydroxynaphthoic acid inhibitors of Plasmodium falciparum lactate dehydrogenase. Med Chem. 2012;8(5): 970-84.
Frecer V, Miertuš S. Polarizable continuum model of solvation for biopolymers. Int J Quantum Chem. 1992;42(5):1449-68.
Böttcher CJF. Theory of electric polarization. Amsterdam, The Netherlands: Elsevier; 1973.
Miertuš S, Scrocco E, Tomasi J. Electrostatic interaction of a solute with a continuum. A direct utilizaion of ab initio molecular potentials for the prevision of solvent effects. Chem Phys. 1981;55(1): 117-29.
Frecer V, Miertuš S. Polarizable continuum model of solvation for biopolymers. Int J Quantum Chem. 1992;42(5):1449-68.
Krovat EM, Frühwirth KH, Langer T. Pharmacophore identification, in silico screening, and virtual library design for inhibitors of the human factor Xa. J Chem Inf Model. 2005;45(1):146-59.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26.
Daily JP. Antimalarial drug therapy: the role of parasite biology and drug resistance. J Clin Pharmacol. 2006;46(12): 1487-97.
Stec J, Vilchèze C, Lun S, Perryman A, Wang X, J. Freundlich et A. Kozikowski, Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. J Med Chem. 2014;9:2528-37.
Jorgensen WL, Duffy EM. Prediction of drug solubility from Monte Carlo simulations. Bioorg Med Chem Lett. 2000;10(11):1155-8.
Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Deliv Rev. 2002;54(3):355-66.
-
Abstract View: 114 times
PDF Download: 34 times
Download Statistics
Downloads
Download data is not yet available.
