Theoretical studies on beta and delta isoform-specific binding mechanisms of phosphoinositide 3-kinase inhibitors

Abstract

Phosphoinositide 3-kinase (PI3K) is known to be closely related to tumorigenesis and cell proliferation, and controls a variety of cellular processes, including proliferation, growth, apoptosis, migration, metabolism, etc. The PI3K family comprises eight catalytic isoforms, which are subdivided into three classes. Recently, the discovery of inhibitors that block a single isoform of PI3K has continued to attract special attention because they may have higher selectivity for certain tumors and less toxicity for healthy cells. The PI3Kβ and PI3Kδ share fewer studies than α/γ, and therefore, in this work, the combination of molecular dynamics simulations and free energy calculations was employed to explore the binding of three isoform-specific PI3K inhibitors (COM8, IC87114, and GDC-0941) to PI3Kβ or PI3Kδ. The isoform specificities of the studied inhibitors derived from the predicted binding free energies are in good agreement with the experimental data. In addition, the key residues critical for PI3Kβ or PI3Kδ selectivity were highlighted by decomposing the binding free energies into the contributions from individual residues. It was observed that although PI3Kβ and PI3Kδ share the conserved ATP-binding pockets, individual residues do behave differently, particularly the residues critical for PI3Kβ or PI3Kδ selectivity. It can be concluded that the inhibitor specificity between PI3Kβ and PI3Kδ is determined by the additive contributions from multiple residues, not just a single one. This study provides valuable information for understanding the isoform-specific binding mechanisms of PI3K inhibitors, and should be useful for the rational design of novel and selective PI3K inhibitors.

Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations

“…According to the previous studies, MM/GBSA usually provides reliable ranking results rather than accurately predicting the absolute binding free energies. [45,54,65] According to the calculation results, COM25 has the strongest inhibition to GSK3β than CDK2 and its predicted binding free energy for GSK3β is the highest. COM23 has lower potency for GSK3β, and its selective activity against CDK2 is lower than COM25.…”

“…The calculated binding affinities are much stronger than the experimental data. According to the previous studies, MM/GBSA usually provides reliable ranking results rather than accurately predicting the absolute binding free energies . According to the calculation results, COM25 has the strongest inhibition to GSK3β than CDK2 and its predicted binding free energy for GSK3β is the highest.…”

“…ΔG GB is calculated using the generalized Born (GB) model with the parameters developed by Onufriev et al (igb = 2) [62] ; ΔG SA is computed based on the solvent-accessible surface area (SASA) estimated with a fast linear combination of the pairwise overlap (LCPO) algorithm using a probe radius of 1.4 Å [63] : ΔG SA = 0.0072 × ΔSASA; −TΔS is the change in the conformational entropy upon ligand binding, which was not considered here due to expensive computational cost and low prediction accuracy. [64,65] In the ΔG GB calculations, the solvent and solute dielectric constants were set to 80 and 1, respectively. All energy components were calculated using the mm_pbsA program of Amber14 based on 1,000 snapshots evenly extracted from 10to 20-ns MD trajectories.…”

Rational Design of Novel Phosphoinositide 3‐Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D‐QSAR, Molecular Docking and Molecular Dynamics Simulation

“…ΔG GB was calculated by the Generalized Born (GB) model with the parameters developed by Onufriev et al (igb = 2); [43] ΔG GA was estimated based on the solventaccessible surface area (SASA) with a fast linear combination of the pairwise overlap (LCPO) algorithm using a probe radius of 1.4 Å: [44] ΔG SA = 0.0072 × ΔSASA; À TΔS the change of conformation entropy upon ligand binding would not be calculated here because of expensive computational cost and low prediction accuracy. [45][46][47][48][49] In the ΔG GB calculations, the exterior dielectric constant was set to 80, and the solute dielectric constant was set to 1. [50,51] All energy components were calculated using the MM_PBSA program of AMBER16 based on 5000 snapshots evenly extracted from 50 to 100 ns.…”

Computer-Aided Targeting of the PI3K/Akt/mTOR Pathway: Toxicity Reduction and Therapeutic Opportunities

“…It has been reported that the combinatory effort of comparative molecular field analysis (CoMFA), comparative molecular similarity induces analysis (CoMSIA), docking analysis and MD simulation can elucidate the structure-activity correlation of the inhibitors of p110α, as well as the binding modes of inhibitors at the ATP binding pocket [152]. Furthermore, the free energy calculations are used to select and confirm the isoform-specific inhibitors to p110α, p110β or p110δ, in silico [153,154]. So far, ten PI3K inhibitors of high isoform specificity are under clinical trials [104].…”