title: QSAR and pharmacophore modeling of natural and synthetic antimalarial prodiginines.
abstract: Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds possessing antibacterial, anticancer and immunosuppressive activities and are produced by actinomycetes and other eubacteria. Recently, prodiginines have been reported to possess potent in vitro as well as in vivo antimalarial activity against chloroquine sensitive D6 and multi-drug resistant Dd2 strains of Plasmodium falciparum. In the present paper, a QSAR and pharmacophore modeling for a series of natural and synthetic prodiginines was performed to find out structural features which are crucial for antimalarial activity against these D6 and Dd2 Plasmodium strains. The study indicated that inertia moment 2 length, Kier Chi6 (path) index, kappa 3 index and Wiener topological index plays important role in antimalarial activity against D6 strain whereas descriptors inertia moment 2 length, ADME H-bond donors, VAMP polarization XX component and VAMP quadpole XZ component play important role in antimalarial activity against Dd2 strain. Furthermore, a five-point pharmacophore (ADHRR) model with one H-bond acceptor (A), one H-bond donor (D), one hydrophobic group (H) and two aromatic rings (R) as pharmacophore features was developed for D6 strain by PHASE module of Schrodinger suite. Similarly a six-point pharmacophore AADDRR was developed for Dd2 strain activity. All developed QSAR models showed good correlation coefficient (r² > 0.7), higher F value (F >20) and excellent predictive power (Q² > 0.6). Developed models will be highly useful for predicting antimalarial activity of new compounds and could help in designing better molecules with enhanced antimalarial activity. Furthermore, calculated ADME properties indicated drug-likeness of prodiginines.
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
authors.forename: Baljinder
authors.initials: B
authors.lastname: Singh
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D017076:Computer-Aided Design; D015195:Drug Design; D018432:Drug Resistance, Multiple; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials; C010307:prodiginine; D011353:Prodigiosin