Development of quinoline‐based hybrid as inhibitor of methionine aminopeptidase 1 from Leishmania donovani. (7th September 2020)

• Record Type: Journal Article
• Authors: Bhat, Saleem Yousuf; Bhandari, Sonal; Thacker, Pavitra Suresh; Arifuddin, Mohammed; Qureshi, Insaf Ahmed
• Is Part Of: Chemical biology & drug design. Volume 97:Number 2(2021)
• Page Start: 315
• Page End: 324
• Publication Date: 2020-09-07
• Subjects: drug discovery -- in vitro inhibition assay -- Leishmania donovani -- methionine aminopeptidase 1 -- quinoline‐based hybrids; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13783
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N‐terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani ( Ld MetAP1), we have synthesized a series of quinoline‐based hybrids, that is (Z)‐5‐((Z)‐benzylidine)‐2‐(quinolin‐3‐ylimino)thiazolidin‐4‐ones (QYT‐4a‐i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT‐4h) against Ld MetAP1. The compound QYT‐4h showed nearly 20‐fold less potency for human MetAP1 and had drug‐like features. Time–course kinetic assays suggested QYT‐4h acting through a competitive mode by binding to the metal‐activated catalytic site. Notably, QYT‐4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of Ld MetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT‐4h for Ld MetAP1. Through molecular modelling and docking studies, we found QYT‐4h binding at the Ld MetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small‐molecule inhibitors for selective targeting of Ld MetAP1 which may find use to effectively eliminate leishmaniasis. Abstract : A series of quinoline‐based hybrids (QYT‐4a‐i) were synthesized with compound QYT‐4h inhibiting leishmanial MetAP1 ( Ld MetAP1) potently, which was 20‐fold less effective against its human counterpart. The compound QYT‐4h acts upon Ld MetAP1 through a competitive mode of action and is more efficient towards its physiologically relevant Mn(II) and Fe(II) forms. It also exhibits druglikeness, high affinity for Ld MetAP1 and forms a very stable complex with the leishmanial protein.