A linear discrimination analysis based virtual screening of trichomonacidal lead-like compounds: outcomes of in silico studies supported by experimental results.
A computational (virtual) screening test to identify potential trichomonacidals has been developed. Molecular structures of trichomonacidal and non-trichomonacidal drugs were represented using stochastic and non-stochastic atom-based quadratic indices and a linear discrimination analysis (LDA) was trained to classify molecules regarding their antiprotozoan activity. Validation tests revealed that our LDA-QSAR models recognize at least 88.24% of trichomonacidal lead-like compounds and suggest using this methodology in virtual screening protocols. These classification functions were then applied to find new lead antitrichomonal compounds. In this connection, the biological assays of eight compounds, selected by computational screening using the present models, give good results (87.50% of good classification). In general, most of the compounds showed high activity against Trichomonas vaginalis at the concentration of 100 microg/ml and low cytotoxicity to this concentration. In particular, two heterocyclic derivatives (VA7-67 and VA7-69) maintained their efficacy at 10 microg/ml with an important trichomonacidal activity (100.00% of reduction), but it is remarkable that the compound VA7-67 did not show cytotoxic effects in macrophage cultivations. This result opens a door to a virtual study considering a higher variability of the structural core already evaluated, as well as of other chemicals not included in this study.
Meneses-Marcel
Alfredo
A
Department of Parasitology, Chemical Bioactive Center, Central University of Las Villas, 54830 Villa Clara, Cuba.
Marrero-Ponce
Yovani
Y
Machado-Tugores
Yanetsy
Y
Montero-Torres
Alina
A
Pereira
David Montero
DM
Escario
José Antonio
JA
Nogal-Ruiz
Juan José
JJ
Ochoa
Carmen
C
Arán
Vicente J
VJ
Martínez-Fernández
Antonio R
AR
García Sánchez
Rory N
RN
D000818:Animals; D000994:Antitrichomonal Agents / Q000737:chemistry* / Q000145:classification; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014246:Trichomonas vaginalis / Q000187:drug effects; D014584:User-Computer Interface
D000994:Antitrichomonal Agents; D006571:Heterocyclic Compounds