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Toll-like receptor 7 (TLR7) is activated in response to the binding of single-stranded RNA. Its over-activation has been implicated in several autoimmune disorders, and thus, it is an established therapeutic target in such circumstances. TLR7 small-molecule antagonists are not yet available for therapeutic use. We conducted a ligand-based drug design of new TLR7 antagonists through a concerted effort encompassing 2D-QSAR, 3D-QSAR, and pharmacophore modelling of 54 reported TLR7 antagonists. The developed 2D-QSAR model depicted an excellent correlation coefficient (R2training: 0.86 and R2test: 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R2training: 0.95 and R2test: 0.84) demonstrated a significant contribution of electrostatic potential and steric fields towards the TLR7 antagonism. This consolidated approach, along with a pharmacophore model with high correlation (Rtraining: 0.94 and Rtest: 0.92), was used to design quinazoline-core-based hTLR7 antagonists. Subsequently, the newly designed molecules were subjected to molecular docking onto the previously proposed binding model and a molecular dynamics study for a better understanding of their binding pattern. The toxicity profiles and drug-likeness characteristics of the designed compounds were evaluated with in silico ADMET predictions. This ligand-based study contributes towards a better understanding of lead optimization and the future development of potent TLR7 antagonists. [ABSTRACT FROM AUTHOR]

In this paper, we present a formulation of highly correlated Fock-space multi-reference coupled-cluster (FSMRCC) methods, including approximate triples on top of the FSMRCC with singles and doubles, which correct the electron affinities by at least at third and up to the fourth order in perturbation. We discuss various partial fourth-order schemes, which are reliable and yet computationally more efficient than the full fourth-order triples scheme. The third-order scheme is called MRCCSD+T*(3). We present two approximate fourth-order schemes, MRCCSD+T*−a(4) and MRCCSD+T*(4). The results that are presented allow one to choose an appropriate fourth-order scheme, which is less expensive and right for the problem. All these schemes are based on the effective Hamiltonian scheme, and provide a direct calculation of the vertical electron affinities. We apply these schemes to a prototype Li2 molecule, using four different basis sets, as well as BeO and CH+. We have calculated the vertical electron affinities of Li2 at the geometry of the neutral Li2 molecule. We also present the vertical ionization potentials of the Li2 anion at the geometry of the anion ground state. We have also shown how to calculate adiabatic electron affinity, though in that case we lose the advantages of direct calculation. BeO has been examined in two basis sets. For CH+, four different basis sets have been used. We have presented the partial fourth-order schemes to the EA in all the basis sets. The results are analyzed to illustrate the importance of triples, as well as highlight computationally efficient partial fourth-order schemes. The choice of the basis set on the electron affinity calculation is also emphasized. Comparisons with available experimental and theoretical results are presented. The general fourth-order schemes, which are conceptually equivalent with the Fock-space multi-reference coupled-cluster singles, doubles, and triplets (MRCCSD+T) methods, based on bondonic formalism, are also presented here in a composed way, for quantum electronic affinity. [ABSTRACT FROM AUTHOR]

In this paper, we have made a systematic study of partial fourth order perturbative schemes due to triples to compute the ionization potential within Fock-space multi-reference coupled-cluster theory. In particular, we have obtained computationally less expensive correlation schemes due to fourth order triples. Prototype examples have been considered to explore the efficacy of the approximate methods mentioned, while the bondonic formalism supporting the bonding phenomenology is also respectively for the first time here advanced. [ABSTRACT FROM AUTHOR]