Saddle point localization of molecular wavefunctions

The quantum mechanical description of isomerization is based on bound eigenstates of the molecular potential energy surface. For the near-minimum regions there is a textbook-based relationship between the potential and eigenenergies. Here we show how the saddle point region that connects the two minima is encoded in the eigenstates of the model quartic potential and in the energy levels of the [H, C, N] potential energy surface. We model the spacing of the eigenenergies with the energy dependent classical oscillation frequency decreasing to zero at the saddle point. The eigenstates with the smallest spacing are localized at the saddle point. The analysis of the HCN???HNC isomerization states shows that the eigenstates with small energy spacing relative to the effective (v1, v3, l) bending potentials are highly localized in the bending coordinate at the transition state. These spectroscopically detectable states represent a chemical marker of the transition state in the eigenenergy spectrum. The method developed here provides a basis for modeling characteristic patterns in the eigenenergy spectrum of bound states

Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators.This work was financially supported by the Spanish Ministry for Science and Innovation (grants CTQ2014-57141-R, CTQ2017-88353-R, and PID2020-113588RB-I00 for S.M.S.; grants BES-2012-053653 for L.P.R., BES-2015-071588 for J.G.C. and PID2021-124983OB-I00 for J.C.M.), the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (MINECO/FEDER; SAF2016-75988-R), and the Community of Madrid (S-2010/BMD-2332) for M.F