title: Selection of molecular descriptors with artificial intelligence for the understanding of HIV-1 protease peptidomimetic inhibitors-activity.
abstract: Quantitative Structure Activity Relationship (QSAR) techniques are used routinely by computational chemists in drug discovery and development to analyze datasets of compounds. Quantitative numerical methods like Partial Least Squares (PLS) and Artificial Neural Networks (ANN) have been used on QSAR to establish correlations between molecular properties and bioactivity. However, ANN may be advantageous over PLS because it considers the interrelations of the modeled variables. This study focused on the HIV-1 Protease (HIV-1 Pr) inhibitors belonging to the peptidomimetic class of compounds. The main objective was to select molecular descriptors with the best predictive value for antiviral potency (Ki). PLS and ANN were used to predict Ki activity of HIV-1 Pr inhibitors and the results were compared. To address the issue of dimensionality reduction, Genetic Algorithms (GA) were used for variable selection and their performance was compared against that of ANN. Finally, the structure of the optimum ANN achieving the highest Pearson's-R coefficient was determined. On the basis of Pearson's-R, PLS and ANN were compared to determine which exhibits maximum performance. Training and validation of models was performed on 15 random split sets of the master dataset consisted of 231 compounds. For each compound 192 molecular descriptors were considered. The molecular structure and constant of inhibition (Ki) were selected from the NIAID database. Study findings suggested that non-covalent interactions such as hydrophobicity, shape and hydrogen bonding describe well the antiviral activity of the HIV-1 Pr compounds. The significance of lipophilicity and relationship to HIV-1 associated hyperlipidemia and lipodystrophy syndrome warrant further investigation.
authors.affiliation: Immune Deficiency Treatment Centre (IDTC), Montreal General Hospital, Quebec, H3G 1A4, Canada. ssirois@muhc.mcgill.ca
authors.forename: S
authors.initials: S
authors.lastname: Sirois
authors.forename: C M
authors.initials: CM
authors.lastname: Tsoukas
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wei
authors.forename: C
authors.initials: C
authors.lastname: Boucher
authors.forename: G E
authors.initials: GE
authors.lastname: Hatzakis
mesh_terms: D000465:Algorithms; D001185:Artificial Intelligence; D003198:Computer Simulation; D019992:Databases as Topic; D015195:Drug Design; D005823:Genetics; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016018:Least-Squares Analysis; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry* / Q000145:classification; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D010455:Peptides; D016333:HIV Protease