Computational Drug Design and Synthesis - Biophysical Chemistry - Computational Organic Chemistry

Quantum chemical data for developing chemical bases data

The evaluation of various computational chemistry methods, molecular mechanics calculations, ab-initio QM methods, on their ability to predict the experimental conformational preferences of organic molecules and drugs. Example of a subset of compounds and conformational energies is given in Table 1.

A total of 160 conformational energies from 151 model organic molecules were examined and many conformational update aspects were outlined. The data set of the organic molecules included hydrocarbons, haloalkanes, oxygen containing compounds, nitrogen containing compounds, conjugated compounds, phosphorus and sulphur containing compounds. The study allowed the comparison of some standard force fields with wide distribution in commercial and free software for the calculation of conformational energies. The molecules were energy minimized and a number of conformational energies and barriers for the compounds were calculated using UFF, DREIDING, MM2-91 in the form of MM2, MMX, MMFF94, MM3-96, MM3-00, MM4. The performance might be interesting for the force field used from algorithms to produce conformations before docking.

The energies were also calculated using B3LYP/6-31G(d,p), MP2/6-31G(d,p) and also with very accurate theory DLPNO-CCSD(T)/cc-pVTZ using ORCA software at the limit of the correlation energy which has never been applied (with Professor D. Pantazis, Germany).

Table 1. Relative conformational energies of some intramolecular barriers (kcal mol^-1).

Gold-catalyzed reactions

• Study of transition metal catalyzed mechanisms using DFT methods and appropriate algorithms for transition states investigation in the potential energy surface. We studied the gold-catalyzed cycloisomerization of functionalized allenes (Scheme 1) (with Associate Professor C. Silva, Organic  Chemistry, Vigo, Spain).

Scheme 1. Computational study of gold-catalyzed cycloisomerization of functionalized allenes.

• We are currently investigation the [4+2]-type reaction of pyrrole with 1,3-diynes catalyzed by gold leading to 1,4-disubstituted indoles. The calculations suggested  mechanism included a first step of intermolecular hydroarylation leading to an enyne-type intermediate, followed by a second step of an intramolecular hydroarylation. The reactivity profile of indole against the 1,4-diphenyl-butane-1,3-diyne and the different possible reaction pathways are  presented in Schemes 2, 3.

Scheme 2. Relative free energies (kcal/mol, 298 K and 1 atm) computed the alternative reaction pathways in the formal [4+2] reaction between pyrrole and diynes including protodeauration steps of key intermediates.

Scheme 3. Reactivity profile of indole with 1,3-diyne. Relative energies used compound 11a as the zero energy reference.