An integrated drug development approach applying topological descriptors.
We describe the opportunities posed by computer-assisted drug design in the light of two aspects of the current drug discovery scenario: the decline of innovation due to high attrition rates at clinical stage of development and the combinatorial explosion emerging from exponential growth of feasible small molecules and genome and proteome exploration. We present an overview of recent reports from our group in the field of rational drug development, by using topological descriptors (either alone, or in combination with different 3D approaches) and a diversity of modeling techniques such as Linear Discriminant Analysis and the Replacement Method. Modeling efforts aimed at the integrated prediction of several significant molecular properties in the field of drug discovery, such as pharmacological activity, aqueous solubility, human intestinal permeability and affinity to P-glycoprotein (ABCB1, MDR1) are reviewed. The suitability of conformation-independent descriptors to explore large chemical repositories is highlighted, as well as the opportunities posed by in silico guided drug repurposing.
Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata (UNLP), 47 & 115, La Plata (B1900AJI), Buenos Aires, Argentina.
Alan
A
Talevi
Carolina L
CL
Bellera
Mauricio
M
Di Ianni
Pablo R
PR
Duchowicz
Luis E
LE
Bruno-Blanch
Eduardo A
EA
Castro
D000818:Animals; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010600:Pharmacology; D021281:Quantitative Structure-Activity Relationship
D004364:Pharmaceutical Preparations