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Current Computer-Aided Drug Design


ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

Identification of Multi-kinase Allosteric Inhibitors of Oncogenic Targets EGFR1, PI3K, and BRAF Kinase

Author(s): Kavita Kumari Kakarala* and Kaiser Jamil

Volume 18, Issue 7, 2022

Published on: 23 November, 2022

Page: [506 - 518] Pages: 13

DOI: 10.2174/1573409919666221031110341

Price: $65


Aim: This study aimed to identify promising allosteric inhibitors with the potential to inhibit EGFR1, PI3K, and BRAF kinases as a single agent or in a combination of existing drugs, thus acting as a therapeutic option when traditional drugs fail to give a beneficial response in disease pathology.

Background: Upregulation of EGFR1 activates several downstream signaling pathways, resulting in pathophysiological alterations that contribute to cancer. The RAS/RAF/MEK/ERK (MAPK) and PI3K/Akt/mTOR (PI3K/Akt/mTOR) pathways are major downstream signalling partners induced by EGFR1 activation. Despite their vast importance, allosteric FDA-approved drugs targeting EGFR1 and these pathways are not available.

Objective: The objective of the study is to identify novel multi-kinase small molecules with the potential to inhibit major sites of amplification of cancer signalling pathways, i.e., EGFR1, PI3K/Akt/mTOR, and RAS/RAF/MEK/ERK (MAPK) signalling pathways targeting allosteric sites.

Methods: In silico methods were used to identify the potential inhibitors using EGFR1, PI3, and BRAF crystal structures complexed with allosteric inhibitors. The potential novel molecules were confirmed for their drug-likeness. Their stability of binding was also confirmed using molecular dynamics simulation studies. To eliminate false negatives, this study used a pharmacophore and structure-based targeting method.

Results: The current study was effective in identifying drug-like small molecules, such as ZINC38783966, ZINC01456629, ZINC01456628, and 124173751, 137352549, 137353176, 137352399, 132020316 from ZINC and PubChem database, respectively, with a potential to bind EGFR1 (6DUK), PI3 (4A55) and BRAF (6P3D) at allosteric sites. A 50 ns molecular dynamics investigation also revealed that these potential novel multitarget kinase allosteric inhibitors exhibited stable binding.

Conclusion: Alterations in EGFR1, PI3K/Akt/mTOR, and RAS/RAF/MEK/ERK (MAPK) signalling pathways are observed in cancers in high frequency and are also used by viral and environmental toxicants for pathologic purposes. These multi-kinase allosteric inhibitors will provide insight into allosteric drug discovery and deepen our understanding of targeting these pathways, either individually or in combination with orthosteric inhibitors.

Keywords: Kinase, multi-kinase, docking, scoring, free energy, binding affinity, drug-like.

Graphical Abstract
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