Identification of Novel Fourth-Generation Allosteric Inhibitors Targeting Inactive State of EGFR T790M/L858R/C797S and T790M/L858R Mutations: A Combined Machine Learning and Molecular Dynamics Approach.

Targeted therapy with an allosteric inhibitor (AIs) is an important area of research in patients with epidermal growth factor receptor (EGFR) mutations. Current treatment of nonsmall cell lung cancer patients with EGFR mutations using orthosteric inhibitors faces challenges like resistance and stopping over phosphorylation. Notably AIs have been introduced to overcome this resistance and increase inhibitory potency that binds to pockets other than the ATP-binding site (orthosteric site).

Uncovering the Structural and Binding Insights of Dual Inhibitors Simultaneously Targeting Two Distinct Sites on EGFR Kinase.

Epidermal growth factor receptor (EGFR) is the first growth factor receptor identified in normal cells that is related to the receptor tyrosine kinase, which causes regular cell division. A point mutation in EGFR intracellular kinase domain forces the abnormal cell divisions throughout time, leading to non-small cell lung cancer (NSCLC) transformation. Thus, competitive inhibitors that bind to the ATP binding pocket have been developed as a targeted therapy for NSCLC.

Structural insight into G2019S mutated LRRK2 kinase and brain-penetrant type I inhibitor complex: a molecular dynamics approach.

More than 40 mutations in the multidomain leucine-rich repeat kinase 2 (LRRK2) are found and mutation G2019S in the kinase domain is the most concerned with Parkinson's disease (PD). The discovery of the various types of inhibitors has largely emerged recently. However, the comparative study on molecular insight in WT and G2019S LRRK2 kinase domain upon binding of the inhibitors has not yet been explored in detail.

Role of the Residue Q1919 in Increasing Kinase Activity of G2019S LRRK2 Kinase: A Computational Study.

Mutations in multi-domain leucine-rich repeat kinase 2 (LRRK2) have been an interest to researchers as these mutations are associated with Parkinson's disease. G2019S mutation in LRRK2 kinase domain leads to the formation of additional hydrogen bonds by S2019 which results in stabilization of the active state of the kinase, thereby increasing kinase activity. Two additional hydrogen bonds of S2019 are reported separately.