title: To be drug or prodrug: structure-property exploratory approach regarding oral bioavailability.
abstract: OBJECTIVE
  Prodrug design is a strategy that can be used to adjust physicochemical properties of drugs in order to overcome pharmacokinetic problems, such as poor oral bioavailability. However, Lipinski´s and Veber´s rules predict whether compounds will have absorption problems even before the design of prodrugs. In this context, our goal was to evaluate the molecular properties which most influenced the absorption process of prodrugs compared to its precursor through exploratory data analysis approach.
  
  
  METHODS
  A variety of prodrugs and respective precursors were randomly selected and classified by its percentage of human intestinal absorption. Subsequently, different molecular properties were calculated and hierarchical cluster analysis (HCA) and principal components analysis (PCA) were carried out.
  
  
  RESULTS
  According to the findings, antiviral, anti-hypertensive, and antibiotic prodrugs exhibited higher absorption levels than their respective precursors. Also, some relevant descriptors (molecular weight, MW, routable bonds, rot_bonds, hydrogen bond acceptors, HBA_count and polar surface area, PSA), which are included in Lipinski´s and Veber´s rules, influenced the separation process between prodrugs and drugs. Furthermore, other molecular properties, such as polarizability (α) and molar refractivity (MR), were pointed out.
  
  
  CONCLUSIONS
  Lipinski´s and Veber´s rules proved to be important to design an orally administered drug but other descriptors should be considered by medicinal chemists in the prodrug designing process.
authors.affiliation: Faculty of Pharmaceutical Sciences University of São Paulo, Brazil.
authors.forename: Mariana Celestina Frojuello Costa Bernstorff
authors.initials: MC
authors.lastname: Damião
authors.forename: Kerly Fernanda Mesquita
authors.initials: KF
authors.lastname: Pasqualoto
authors.forename: Michelle Carneiro
authors.initials: MC
authors.lastname: Polli
authors.forename: Roberto
authors.initials: R
authors.lastname: Parise Filho
mesh_terms: D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D015195:Drug Design; D006801:Humans; D007408:Intestinal Absorption; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000959:Antihypertensive Agents; D000998:Antiviral Agents; D011355:Prodrugs