Binding pose analysis of hydroxyethylamine based β-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors

Westhuizen, C. Johan van der; Greunen, Divan G. van; Cordier, W; Nell, Margo; Steenkamp,; Stander, André; Panayides, Jenny‐Lee; Riley, DL

doi:10.24820/ark.5550190.p011.350

Cited by 3 publications

(1 citation statement)

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“…Surprisingly, in one work done by researchers towards the exploration of potent BACE1 inhibitors, they substituted the inhibitor's planar aromatic benzyl group with that of 1,2,3,4‐tetrahydronapthalene group. The resultant compound showed substantial inhibition, suggesting that they can be used as good substituents towards BACE1 inhibition [54]. Molecular interaction analysis of RJC03532 revealed that OD2 atom of ASP32 establishes hydrogen bond with amino (N10‐H39) group from the quinolin‐4‐amine moiety of the inhibitor, positioned at a distance of 1.615 Å.…”

Section: Resultsmentioning

confidence: 99%

Artificial neural network models driven novel virtual screening workflow for the identification and biological evaluation of BACE1 inhibitors

Kashyap

Panigrahi

Ahmed

et al. 2023

Molecular Informatics

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Beta-site amyloid-β precursor protein-cleaving enzyme 1 (BACE1) is a transmembrane aspartic protease and has shown potential as a possible therapeutic target for Alzheimer's disease. This aggravating disease involves the aberrant production of β amyloid plaques by BACE1 which catalyzes the ratelimiting step by cleaving the amyloid precursor protein (APP), generating the neurotoxic amyloid β protein that aggregates to form plaques leading to neurodegeneration. Therefore, it is indispensable to inhibit BACE1, thus modulating the APP processing. In this study, we present a workflow that utilizes a multi-stage virtual screening protocol for identifying potential BACE1 inhibitors by employing multiple artificial neural network-based models. Collectively, all the hyperparameter tuned models were assigned a task to virtually screen Maybridge library, thus yielding a consensus of 41 hits. The majority of these hits exhibited optimal pharmacokinetic properties confirmed by high central nervous system multiparameter optimization (CNS-MPO) scores. Further shortlisting of 8 compounds by molecular docking into the active site of BACE1 and their subsequent in-vitro evaluation identified 4 compounds as potent BACE1 inhibitors with IC50 values falling in the range 0.028-0.052 μM and can be further optimized with medicinal chemistry efforts to improve their activity.

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Section: Resultsmentioning

confidence: 99%

Artificial neural network models driven novel virtual screening workflow for the identification and biological evaluation of BACE1 inhibitors

Kashyap

Panigrahi

Ahmed

et al. 2023

Molecular Informatics

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Synthesis of Indenoindole Derivatives under Deep Eutectic Solvent Conditions

Kotha,

Salman,

Cheekatla

2024

ChemistrySelect

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In this study, we synthesized a variety of indole derivatives using commercially available 2,5‐dimethoxybenzaldehyde 18 as a starting material. The synthetic route involves a sequential usage of Knoevenagel and Fischer indolization reactions as key steps and the Fischer indolization is facilitated by deep eutectic solvent (DES) such as L‐tartaric acid/dimethylurea (TA:DMU). All the compounds prepared here are characterized by HRMS, 1H‐NMR and 13C‐NMR data. The methodology described in this study showcases the utility of deep eutectic solvents in facilitating the synthesis of diverse indole derivatives, thereby expanding the toolkit of sustainable synthetic methodologies. These compounds are medicinally important and play a key role as an effective template in Kinase inhibitors (CK2). Various functionalized indeno[1,2‐b]indole scaffolds synthesized here might be valuable as novel inhibitors of human CK2. Elevated levels of protein kinase CK2, previously known as casein kinase 2 or II, have been linked to higher cell growth and proliferation in both normal and cancerous cells.

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