Abelson tyrosine-protein kinase 1 as principal target for drug discovery against leukemias. Role of the current computer-aided drug design methodologies.
The discovery of anti-cancer agents is an area which continues in accelerated expansion. Leukemias (Lkms) are among the most investigated cancers due to its high and dominant prevalence in children. Computer-aided drug design (CADD) methodologies have been extremely important for the discovery of potent anti-Lkms agents, providing essential insights about the molecular patterns which could be involved in the appearance and development of anti-Lkms activity. The present review is focused on the role of the current CADD methodologies for the discovery of anti-Lkms agents with strong emphasis on the in silico prediction of inhibitors against the primary protein associated with the appearance of Lkms: Abelson tyrosine-protein kinase 1 (TPK-ABL1). In order to make a contribution to the field, we also developed a unified ligand-based approach by exploring Quantitative-Structure Activity Relationships (QSAR) studies. Here, we focused on the construction of two multi-targets (mt) QSAR models by employing a large and heterogeneous database of compounds. These models exhibited excellent statistical quality and predictive power to classifying more than 92% of inhibitors/ no inhibitors against seven proteins associated with Lkms, in both training and prediction sets. By using our unified ligand-based approach we identified several fragments as responsible for the anti-Lkms activity through inhibition of proteins, and new molecules were suggested as versatile inhibitors of the seven proteins under study.
REQUIMTE/Department of Chemistry and Biochemistry, University of Porto, 4169-007 Porto, Portugal. alejspivanovich@gmail.com
Alejandro
A
Speck-Planche
Feng
F
Luan
M N D S
MN
Cordeiro
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002648:Child; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases