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Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

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Abstract

Serine protease activity of the NS3 protein of Dengue virus is an important target of antiviral agents that interfere with the viral polyprotein precursor processing catalyzed by the NS3 protease (NS3pro), which is important for the viral replication and maturation. Recent studies showed that substrate-based peptidomimetics carrying an electrophilic warhead inhibit the NS2B-NS3pro cofactor-protease complex with inhibition constants in the low micromolar concentration range when basic amino acid residues occupy P1 and P2 positions of the inhibitor, and an aldehyde warhead is attached to the P1. We have used computer-assisted combinatorial techniques to design, focus using the NS2B-NS3pro receptor 3D structure, and in silico screen a virtual library of more than 9,200 peptidomimetic analogs targeted around the template inhibitor Bz-Nle-Lys-Arg-Arg-H (Bz—benzoyl) that are composed mainly of unusual amino acid residues in all positions P1–P4. The most promising virtual hits were analyzed in terms of computed enzyme-inhibitor interactions and Adsorption, Distribution, Metabolism and Excretion (ADME) related physico-chemical properties. Our study can direct the interest of medicinal chemists working on a next generation of antiviral chemotherapeutics against the Dengue Fever towards the explored subset of the chemical space that is predicted to contain peptide aldehydes with NS3pro inhibition potencies in nanomolar range which display ADME-related properties comparable to the training set inhibitors.

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Abbreviations

ADME:

Adsorption distribution metabolism and excretion

CFF91:

Consistent class II force field

DEN2:

Dengue virus serological type 2

DHF:

Dengue hemorrhagic fever

MM:

Molecular mechanics

NS2B:

Nonstructural protein 2B (essential cofactor)

NS3:

Nonstructural protein 3

NS3pro:

Serine protease domain of the NS3 protein

Abu:

α-Aminobutyric acid

Bz:

Benzoyl

Cit:

Citrulline

hHis:

Homo-histidine

N-MeArg:

(N-methyl)-arginine

2Nal:

β-(2-Naphthyl)-alanine

Nle:

Norleucine

Nva:

Norvaline

Orn:

Ornithine

p(Py)Ala:

β-(4-Pyridyl)-alanine

p(Ac)Phe:

(4-N-Acetylamino)-phenylalanine

m(Am)Phe:

(3-Amino)-phenylalanine

p(Am)Phe:

(4-Amino)-phenylalanine

p(Cl)Phe:

(4-Chloro)-phenylalanine

p(CN)Phe:

(4-Cyano)-phenylalanine

m(Gn)Phe:

(3-Guanidino)-phenylalanine

p(Gn)Phe:

(4-Guanidino)-phenylalanine

m(Im)Phe:

(3-Imino)-phenylalanine

p(Im)Phe:

(4-Imino)-phenylalanine

p(Ip)Phe:

(4-Isopropyl)-phenylalanine

(Md)Phe:

(3,4-Methylenedioxy)-phenylalanine

p(Hm)Phe:

(4-Hydroxymethyl)-phenylalanine

p(Me)Phe:

(4-Methyl)-phenylalanine

(dMo)Phe:

(3,4-Dimethoxy)-phenylalanine

p(Ph)Phe:

(4-Phenyl)-phenylalanine

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Acknowledgments

This work has been done within the ICS-UNIDO global program on Rational Drug Design and Discovery. The institutional support to this work is gratefully acknowledged.

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Authors and Affiliations

  1. International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, 34012, Trieste, Italy

    Vladimir Frecer & Stanislav Miertus

  2. Cancer Research Institute, Slovak Academy of Sciences, 83391, Bratislava, Slovakia

    Vladimir Frecer

  3. Laboratory of Molecular, Biostructural and Nanomaterial Modeling, Consortium AREA Science Park of Trieste, AREA Science Park, 34012, Trieste, Italy

    Vladimir Frecer

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  1. Vladimir Frecer
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Correspondence to Stanislav Miertus.

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Frecer, V., Miertus, S. Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease. J Comput Aided Mol Des 24, 195–212 (2010). https://doi.org/10.1007/s10822-010-9326-8

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