Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases

Leandro Rocha Silva; Ari Souza Guimarães; Jadiely do Nascimento; Igor José do Santos Nascimento; Elany Barbosa da Silva; James H McKerrow; Sílvia Helena Cardoso; Edeildo Ferreira da Silva-Júnior

doi:10.1016/j.bmc.2021.116213

Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases

Bioorg Med Chem. 2021 Jul 1:41:116213. doi: 10.1016/j.bmc.2021.116213. Epub 2021 May 11.

Authors

Leandro Rocha Silva¹, Ari Souza Guimarães¹, Jadiely do Nascimento², Igor José do Santos Nascimento³, Elany Barbosa da Silva⁴, James H McKerrow⁴, Sílvia Helena Cardoso², Edeildo Ferreira da Silva-Júnior⁵

Affiliations

¹ Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil; Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca 57309-005, Brazil.
² Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca 57309-005, Brazil.
³ Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil.
⁴ Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
⁵ Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil. Electronic address: [email protected].

PMID: 33992862
DOI: 10.1016/j.bmc.2021.116213

Abstract

Chagas disease and Human African Trypanosomiasis (HAT) are caused by Trypanosoma cruzi and T. brucei parasites, respectively. Cruzain (CRZ) and Rhodesain (RhD) are cysteine proteases that share 70% of identity and play vital functions in these parasites. These macromolecules represent promising targets for designing new inhibitors. In this context, 26 CRZ and 5 RhD 3D-structures were evaluated by molecular redocking to identify the most accurate one to be utilized as a target. Posteriorly, a virtual screening of a library containing 120 small natural and nature-based compounds was performed on both of them. In total, 14 naphthoquinone-based analogs were identified, synthesized, and biologically evaluated. In total, five compounds were active against RhD, being three of them also active on CRZ. A derivative of 1,4-naphthoquinonepyridin-2-ylsulfonamide was found to be the most active molecule, exhibiting IC₅₀ values of 6.3 and 1.8 µM for CRZ and RhD, respectively. Dynamic simulations at 100 ns demonstrated good stability and do not alter the targets' structures. MM-PBSA calculations revealed that it presents a higher affinity for RhD (-25.3 Kcal mol^-1) than CRZ, in which van der Waals interactions were more relevant. A mechanistic hypothesis (via C3-Michael-addition reaction) involving a covalent mode of inhibition for this compound towards RhD was investigated by covalent molecular docking and DFT B3LYP/6-31 + G* calculations, exhibiting a low activation energy (ΔG^‡) and providing a stable product (ΔG), with values of 7.78 and - 39.72 Kcal mol^-1, respectively; similar to data found in the literature. Nevertheless, a reversibility assay by dilution revealed that JN-11 is a time-dependent and reversible inhibitor. Finally, this study applies modern computer-aided techniques to identify promising inhibitors from a well-known chemical class of natural products. Then, this work could inspire other future studies in the field, being useful for designing potent naphthoquinones as RhD inhibitors.

Keywords: Cysteine protease; DFT; Drug design; MM-PBSA; Naphthoquinone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Naphthylamine / analogs & derivatives
Aminoquinolines
Computer-Aided Design*
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Drug Design*
Drug Discovery
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Protein Conformation
Protozoan Proteins / antagonists & inhibitors*
Small Molecule Libraries*
Structure-Activity Relationship
Trypanocidal Agents / chemistry
Trypanocidal Agents / pharmacology
Trypanosoma cruzi / drug effects
Trypanosoma cruzi / enzymology

Substances

Aminoquinolines
Cysteine Proteinase Inhibitors
Protozoan Proteins
Small Molecule Libraries
Trypanocidal Agents
naphthoquine
1-Naphthylamine
Cysteine Endopeptidases
rhodesain
cruzipain