A physicochemical descriptor based method for effective and rapid screening of dual inhibitors against BACE-1 and GSK-3β as targets for Alzheimer's disease. (December 2017)

• Record Type: Journal Article
• Authors: Kumar, Akhil; Srivastava, Gaurava; Sharma, Ashok
• Is Part Of: Computational biology and chemistry. Volume 71(2017)
• Page Start: 1
• Page End: 9
• Publication Date: 2017-12
• Subjects: AD Alzheimer' disease -- BACE-1 β-secreatse -- GSK-3β glycogen synthase kinase-3β -- N nitrogen -- O oxygen -- Cl chlorine -- F fluorine -- S sulphur -- P phosphorus -- C carbon -- HBA hydrogen bond acceptors -- HBD hydrogen bond donors -- TPSA topological polar surface area; Alzheimer's disease -- BACE-1 -- GSK-3β -- Virtual screening -- Physicochemical properties; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2017.09.001
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: Chemical space distribution for BACE-1 and GSK-3β inhibitors. Physiochemical descriptor based filtering to identify dual inhibitor. Reduces the virtual screened database size and time. Abstract: Due to multifactorial nature of Alzheimer's disease one target-one ligand hypothesis often looks insufficient. BACE-1 and GSK-3β are well established therapeutic drug targets and interaction between BACE-1 and GSK-3β pathways has also been established. Thus, designing of dual inhibitor for these two targets seems rational and may provide effective therapeutic strategies against AD. Recent studies revealed that only two scaffolds i.e. triazinone and curcumin act as a dual inhibitor against BACE-1 and GSK-3β. Thus, this discovery set the path to screen new chemical entities from a vast chemical space (∼10 60 compounds) that inhibit both the targets. However, small part of the large chemical space will only show biological activity for specific targets. Virtual screening of large libraries is impractical and computational expensive especially in case of dual inhibitor design. In the case of dual or multi target inhibitor designing, we screened the database for each target that further increases time and resources. In this study we have done physicochemical descriptor based profiling to know the biological relevant chemical space for BACE-1 and GSK-3β inhibitors and proposed the suitable range of important physicochemical properties, occurrence of functional groups. We generated scaffolds tree of known inhibitors of BACE-1 and GSK-3β suggesting the common structure/fragment that can be used to design dual inhibitors. This approach can filter the potential dual inhibitor candidates of BACE-1 and GSK-3β from non inhibitors.