Water Bridges Play a Key Role in Affinity and Selectivity for Malarial Protease Falcipain-2
| Autor: | Pedro Geraldo Pascutti, Vitor B. P. Leite, Jorge E. Hernández-González, Lilian Hernández Alvarez |
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| Přispěvatelé: | Universidade Estadual Paulista (Unesp), Univ Calif San Diego, Universidade Federal do Rio de Janeiro (UFRJ) |
| Rok vydání: | 2020 |
| Předmět: |
Peptidomimetic
General Chemical Engineering medicine.medical_treatment Drug target Plasmodium falciparum Library and Information Sciences Cysteine Proteinase Inhibitors 01 natural sciences Antimalarials parasitic diseases 0103 physical sciences medicine Moiety Humans Protease 010304 chemical physics biology Chemistry Water General Chemistry biology.organism_classification 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Cysteine Endopeptidases Biochemistry Selectivity Peptide Hydrolases |
| Zdroj: | Web of Science Repositório Institucional da UNESP Universidade Estadual Paulista (UNESP) instacron:UNESP |
| ISSN: | 1549-960X |
| Popis: | Made available in DSpace on 2021-06-25T12:27:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-23 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Falcipain-2 (FP-2) is hemoglobinase considered an attractive drug target of Plasmodium falciparum. Recently, it has been shown that peptidomimetic nitriles containing a 3-pyridyl (3Pyr) moiety at P2 display high affinity and selectivity for FP-2 with respect to human cysteine cathepsins (hCats), outperforming other P2 Pyr isomers and analogs. Further characterization demonstrated that certain P3 variants of these compounds possess micromolar inhibition of parasite growth in vitro and no cytotoxicity against human cell lines. However, the structural determinants underlying the selectivity of the 3Pyr-containing nitriles for FP-2 remain unknown. In this work, we conduct a thorough computational study combining MD simulations and free energy calculations to decipher the bases of the selectivity of the aforementioned nitriles. Our results reveal that water bridges involving the nitrogen and one carboxyl oxygen of I85 and D234 of FP-2, respectively, and the nitrogen of the neutral 3Pyr moiety, which are either less prevalent or nonexistent in the other complexes, explain the experimental activity profiles. The presence of crystallographic waters close to the bridging water positions in the studied proteases strongly supports the occurrence of such interactions. Overall, our findings suggest that selective FP-2 inhibitors can be designed by promoting water bridge formation at the bottom of the S2 subsite and/or by introducing complementary groups that displace the bridging water. Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Fis, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Ctr Discovery & Innovat Parasit Dis, La Jolla, CA 92093 USA Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Modelagem & Dinam Mol, Ave Carlos Chagas Filho 373,CCS Bloco D Sala 30, BR-21941902 Rio De Janeiro, Brazil Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Fis, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil FAPESP: 2016/24587-9 FAPESP: 2018/03911-8 FAPESP: 2018/25311-2 CAPES: 001 |
| Databáze: | OpenAIRE |
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