Water Bridges Play a Key Role in Affinity and Selectivity for Malarial Protease Falcipain-2

Author(s)

Gonzalez, Jorge Enrique Hernandez ^[1] ; Alvarez, Lilian Hernandez ^{[1, 2]} ; Leite, Vitor B. P. ^[1] ; Pascutti, Pedro Geraldo ^[3]

Affiliation

^[1] Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Fis, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[2] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Ctr Discovery & Innovat Parasit Dis, La Jolla, CA 92093 - USA

^[3] 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

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 11, p. 5499-5512, NOV 23 2020.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 16/24587-9 - In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3
• Grantee: Jorge Enrique Hernández González
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/25311-2 - Pharmacological characterization and optimization of novel natural compounds with anti-Chagas activity
• Grantee: Lilian Hernández Alvarez
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 18/03911-8 - Structure-based design of competitive and allosteric inhibitors of cruzain
• Grantee: Lilian Hernández Alvarez
• Support Opportunities: Scholarships in Brazil - Doctorate