Title:Identification of Multi-kinase Allosteric Inhibitors of Oncogenic Targets
EGFR1, PI3K, and BRAF Kinase
Volume: 18
Issue: 7
Author(s): Kavita Kumari Kakarala*Kaiser Jamil
Affiliation:
- Bhagawan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, AC Guards, Lakdikapul, Hyderabad, Telangana
500004, India
Keywords:
Kinase, multi-kinase, docking, scoring, free energy, binding affinity, drug-like.
Abstract:
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.
