ABSTRACT
The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand-protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design. Nevertheless, the fragment molecular orbital (FMO) method has gained widespread application in drug design due to its ability to reduce computational costs and achieve efficient ab initio QM calculations. Although the FMO method has demonstrated its reliability in calculating the gas phase potential energy, the binding of proteins and ligands also involves other contributing energy terms, such as solvent effects, the 'deformation energy' of a ligand's bioactive conformations, and entropy. Particularly in cases involving ionized fragments, the calculation of solvation free energy becomes particularly crucial. We conducted an evaluation of some previously reported implicit solvent methods on the same data set to assess their potential for improving the performance of the FMO method. Herein, we develop a new QM-based binding free energy calculation method called FMOScore, which enhances the performance of the FMO method. The FMOScore method incorporates linear fitting of various terms, including gas-phase potential energy, deformation energy, and solvation free energy. Compared to other widely used traditional prediction methods such as FEP+, MM/PBSA, MM/GBSA, and Autodock vina, FMOScore showed good performance in prediction accuracies. By constructing a retrospective case study, it was observed that incorporating calculations for solvation free energy and deformation energy can further enhance the precision of FMO predictions for binding affinity. Furthermore, using FMOScore-guided lead optimization against Src homology-2-containing protein tyrosine phosphatase 2 (SHP-2), we discovered a novel and potent allosteric SHP-2 inhibitor (compound 8).
Subject(s)
Entropy , Ligands , Reproducibility of Results , Retrospective Studies , SolventsABSTRACT
Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/C797S (IC50 = 0.75 µM) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 µM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.
Subject(s)
Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Protein Kinase Inhibitors , Quinazolines , Humans , Adenosine Triphosphate/metabolism , Allosteric Site , Binding Sites , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Drug DiscoveryABSTRACT
OBJECTIVES: To study the difference in cognitive impairment between the children with benign childhood epilepsy with centrotemporal spikes (BECT) and attention deficit hyperactivity disorder (ADHD) and those with BECT or ADHD alone. METHODS: A prospective study was performed on 80 children with BECT and ADHD, 91 children with BECT, and 70 children with ADHD , who were diagnosed with the diseases for the first time. Seventy children of the same age who underwent physical examination were enrolled as the healthy control group. Event-related potential P300, Wechsler Intelligence Scale for Children, and integrated visual and auditory continuous performance test were used to measure and compare each index between groups. RESULTS: Compared with the healthy control group, the BECT+ADHD group, the BECT group, and the ADHD group had a significantly prolonged P300 latency, a significant reduction in the amplitude of P300, and significant reductions in the scores of verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), processing speed index (PSI), full scale intelligence quotient (FSIQ), auditory response control quotient (ARCQ), visual response control quotient, full response control quotient (FRCQ), auditory attention quotient (AAQ), visual attention quotient, and full attention quotient (P<0.05). Compared with the BECT group, the BECT+ADHD group had a significantly prolonged P300 latency, a significant reduction in the amplitude of P300, and significant reductions in the scores of VCI, PRI, WMI, PSI, FSIQ, and FRCQ (P<0.05). Compared with the ADHD group, the BECT+ADHD group had a significantly prolonged P300 latency, a significant reduction in the amplitude of P300, and significant reductions in the scores of VCI, PRI, FSIQ, ARCQ, FRCQ, and AAQ (P<0.05). CONCLUSIONS: Compared with the children with BECT or ADHD alone, the children with both BECT and ADHD have basically the same fields of cognitive impairment but a higher degree of cognitive impairment in some fields.