Active site specific pharmacophore-based screening for methyltransferase inhibitors

Abstract

BackgroundDengue hemorrhagic fever is a mosquito-borne, re-emerging infectious disease in many areas of the world, which affects 50–100 million human and causes 24,000 deaths every year. Currently, no specific drug is available for dengue fever. Dengue fever is caused by Flavivirus. Methyltransferase (MTase) is particularly important for viral replication, which also plays a key role in normal physiology and human infection through methylating DNA. The flaviviral MTase (NS5) which catalyzes both guanine N-7 and ribose 2′-OH methylation during viral cap formation, serve as a promising flavivirus drug target. The present work is to identify lead molecules for Flavivirus NS5 MTase using computational approaches like structure-based pharmacophore and induced fit docking. MethodsEnergy-optimized pharmacophore models were generated for the RTP, SAH and SAM ligands based on their binding mode at the different parts of the active site of MTase. Pharmacophore-based screening of the Asinex database was performed. The short-listed compounds were subjected for induced fit docking. ResultsThe pharmacophore sites were predicted for RTP, SAH and SAM with seven features of which, minimum of three pharmacophore features were taken as the basis for screening the ligands. At the end of docking analysis, three compounds having high binding capability for RTP, SAH and SAM binding sites of MTase were observed. ConclusionsThese results suggest that the selected compounds could be novel leads to inhibit MTase and may stop viral replication further. Also, these three lead compounds could be serving as building blocks for designing drug-like molecules for the treatment of dengue hemorrhagic fever.