Title:Exploring Structural Requirements for a Class of Nucleoside Inhibitors (PfdUTPase) as Antimalarials: First Report on QSAR, Pharmacophore Mapping and Multiple Docking Studies
Volume: 16
Issue: 9
Author(s): Probir Kumar Ojha and Kunal Roy
Affiliation:
Keywords:
Docking, malaria, nucleoside analogs, PfdUTPase, pharmacophore, QSAR.
Abstract: Multi-drug resistance to the available antimalarial drugs is a major threat for malaria treatment. Due to the
recent characterization of human and parasite genome sequences, both ligand and target based drug design strategies may
be helpful for the design of potential antimalarial compounds with reduced degree of resistance. The present work deals
with quantitative structure-activity relationship (QSAR) modeling, pharmacophore mapping and docking studies of a
series of 95 nucleoside analogs as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase
(PfdUTPase), an enzyme involved in nucleotide metabolism that acts as a first line of defence against uracil incorporation
into DNA. The QSAR and pharmacophore models were validated both internally and externally showing good statistical
results. The docking study was performed and validated using three different software tools namely Discovery Studio 2.1
(Accelrys), Maestro 9.3 (Schrodinger) and MOE (Chemical Computing Group). The QSAR studies revealed that
compounds containing substituted aromatic carbons (aasC fragment) and those bearing hydroxyl groups without an noxolane
ring exert potent PfdUTPase inhibitory activity. The best pharmacophore hypothesis (hypothesis 1) possessed
four features: (i) one hydrogen bond donor (HBD), (ii) one hydrogen bond acceptor (HBA), (iii) one hydrophobic (HYD)
and (iv) one ring aromatic (RA). The docking studies revealed that the PfdUTPase inhibitors interact with a pocket
containing Phe46, Lys48, Leu88, Asn103, Gly106, Leu107, Ile108, Tyr112, Ile116, Ile117, Ala118 and Ala119 amino
acid residues. The interaction pattern of all the PfdUTPase inhibitors was almost same in case of docking using Discovery
Studio 2.1, Maestro 9.3 and MOE software. This work thus presents the first QSAR report for nucleoside analogs which
may serve as an efficient tool to address the increasing threat of malaria in the developing countries.
