Conformational Restriction and Steric Hindrance in Medicinal Chemistry

Wipf, Peter; Skoda, Erin M.; Mann, André

doi:10.1016/b978-0-12-417205-0.00011-0

Cited by 40 publications

(54 citation statements)

References 94 publications

(80 reference statements)

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“…In contrast, a structural analog without methyl groups on the D ring displays free bond rotation on the NMR timescale (~ nanoseconds). Typically such barriers to rotation at room temperature correspond to ~ 5 kcal/mol (LaPlante et al, 2011a;LaPlante et al, 2011b;Wipf et al, 2015). The NMR spectrum of the ensemble of rapidly exchanging conformations reflects the Boltzmann weighted average of the chemical shifts, J-couplings, and interproton distances, with a single set of sharp peaks.…”

Section: Nmr Measured Rotational Energy Barriermentioning

confidence: 99%

Comment on mr-2021-27

2021

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Section: Nmr Measured Rotational Energy Barriermentioning

confidence: 99%

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2021

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“…Therefore, we proposed increasing the affinity of the inhibitors to the binding site by using the 6-phenylthieno [2,3-d]pyrimidine as a core scaffold and a hinge binder. The phenylthiophene is assumed to bind in the hydrophobic pocket II fulfilling the hydrophobic interactions with the surrounding residues (Figure 4), the increased hydrophobicity of the phenylthiophene compared to the corresponding phenylfuran in lapatinib is hypothesized to increase the ligand affinity through strengthening the hydrophobic interactions contributing to the enthalpic component of the binding free energy, in addition to an entropic contribution through its favorable desolvation effect [31]. Meanwhile, the N-1 of the pyrimidine is proposed to interact with Met793/EGFR or Met801/HER2 of the hinge region through hydrogen bonds, and N-3 is expected to form a water-mediated hydrogen bond with Thr854/EGFR or Thr862/HER2 (Figure 4).…”

Section: Rationale and Designmentioning

confidence: 99%

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

Milik

Abdel-Aziz

Lasheen

et al. 2018

European Journal of Medicinal Chemistry

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In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.

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“…The sum of square differences determines the goodness-of-fit between experimental and calculated values to select a best-fit population-weighted model. The fundamental concept of filtering theoretical conformations through experimental data to derive the best fit has become well established over the decades, together with variations in details of implementation, to determine the conformational preference(s) of a small molecule in solution (Cicero et al, 1995;Nevins et al, 1999;Slabber et al, 2016;Wu et al, 2017;Balazs et al, 2019;Farès et al, 2019;Atilaw et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Nuclear magnetic resonance free ligand conformations and atomic resolution dynamics

et al. 2021

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Abstract. Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion angles, by replica exchange with solute tempering molecular dynamics (REST-MD), gives results in agreement with high-resolution 1H nuclear magnetic resonance (NMR) spectra and complements free ligand conformational analyses. Rotational energy barriers around individual bonds are comparable between calculated and experimental values, making the in-silico method relevant to ranking prospective design ideas in drug discovery programs, particularly across a series of analogs. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the “right molecules” for effective medicines.

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Conformational Restriction and Steric Hindrance in Medicinal Chemistry

Cited by 40 publications

References 94 publications

Comment on mr-2021-27

Comment on mr-2021-27

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

Nuclear magnetic resonance free ligand conformations and atomic resolution dynamics

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