| Autor: |
Hernández González JE; Departamento de Fı́sica, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista Júlio de Mesquita Filho, Rua Cristóvão Colombo, 2265, Jardim Nazareth, São José do Rio Preto, São Paulo CEP 15054-000, Brazil., Hernández Alvarez L; Departamento de Fı́sica, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista Júlio de Mesquita Filho, Rua Cristóvão Colombo, 2265, Jardim Nazareth, São José do Rio Preto, São Paulo CEP 15054-000, Brazil.; Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, California 92093, United States., Leite VBP; Departamento de Fı́sica, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista Júlio de Mesquita Filho, Rua Cristóvão Colombo, 2265, Jardim Nazareth, São José do Rio Preto, São Paulo CEP 15054-000, Brazil., Pascutti PG; Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofı́sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Ave. Carlos Chagas Filho, 373, CCS-Bloco D sala 30, Cidade Universitária Ilha de Fundão Rio de Janeiro, CEP 21941-902, Brazil. |
| Abstrakt: |
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. |
