title: Comparative molecular surface analysis (CoMSA) for virtual combinatorial library screening of styrylquinoline HIV-1 blocking agents.
abstract: We used comparative molecular surface analysis to design molecules for the synthesis as part of the search for new HIV-1 integrase inhibitors. We analyzed the virtual combinatorial library (VCL) constituted from various moieties of styrylquinoline and styrylquinazoline inhibitors. Since imines can be applied in a strategy of dynamic combinatorial chemistry (DCC), we also tested similar compounds in which the -C=N- or -N=C- linker connected the heteroaromatic and aromatic moieties. We then used principal component analysis (PCA) or self-organizing maps (SOM), namely, the Kohonen neural networks to obtain a clustering plot analyzing the diversity of the VCL formed. Previously synthesized compounds of known activity, used as molecular probes, were projected onto this plot, which provided a set of promising virtual drugs. Moreover, we further modified the above mentioned VCL to include the single bond linker -C-N- or -N-C-. This allowed increasing compound stability but expanded also the diversity between the available molecular probes and virtual targets. The application of the CoMSA with SOM indicated important differences between such compounds and active molecular probes. We synthesized such compounds to verify the computational predictions.
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, University of Silesia, Katowice, Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Niedbala
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Polanski
authors.forename: Rafal
authors.initials: R
authors.lastname: Gieleciak
authors.forename: Robert
authors.initials: R
authors.lastname: Musiol
authors.forename: Dominik
authors.initials: D
authors.lastname: Tabak
authors.forename: Barbara
authors.initials: B
authors.lastname: Podeszwa
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bak
authors.forename: Anna
authors.initials: A
authors.lastname: Palka
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: Johann
authors.initials: J
authors.lastname: Gasteiger
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bret
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000187:drug effects; D015394:Molecular Structure; D016571:Neural Networks, Computer; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D013499:Surface Properties
chemical_list: D019380:Anti-HIV Agents; D011804:Quinolines; C481600:styrylquinoline; D019427:HIV Integrase