A conformational analysis of the (3S,5R,6R)-6-acetylamidopenicillanic acid was performed using AM1, omega, and PM3 conformers. Their geometries were optimized at the ab initio HF/STO-3G level. The AM1 semiempirical MO method yields only eight conformers, the PM3 and Omega methods give 47 conformers, while the ab initio HF/STO-3G method leads to 28 conformers. For comparing the geometry of these conformers three geometrical properties were considered: the pseudo-chirality at N atom of the exocyclic amidic group, the anti/syn conformation of the O and H atoms from the exocyclic amidic group, and the three puckering classes of the thiazolidinic ring. The HF/STO-3G geometries do not differ significantly from the experimental ones or from those obtained by other authors who used basis sets of higher performance. However, unlike the high performant basis sets which tend to equalize the S1..C9 and S1..C10 distances, the HF/STO-3G basis set is able to distinguish between these bond lengths, namely the S1..C9 distance is larger than S1..C10. From this conformational analysis it resulted that the HF/STO-3G conformers belonging to the puckering classes (a) and (b) have the most favourable geometrical properties needed for the conversion of penicillins to cephalosporins.

28 distinct conformers of the (3S,5S,6S)-6-acetylamidopenicillanic acid previously optimized at HF/STO-3G ab initio level were energetically minimized with the PM6 and PM7 semiempirical MO methods included in the MOPAC12 software. After energy minimization 14, respectively 19 distinct conformers were obtained. The difference (∆Hform(298)) between the lowest and the highest standard formation enthalpy of conformers is 4.42 kcal/mol, and 7.03 kcal/mol for PM6, and PM7 semiempirical MO methods, respectively. For the conformers obtained by the PM6 and PM7 semiempirical MO methods quadratic interpolation relations of functional dependence of formation enthalpy on temperature (∆Hform = a0 + a1T + a2T) were established. The a1 and a2 values are neither dependent on the method of calculation, nor the conformer geometry. The a0 free term is the only one which depends on the conformer geometry. It increases with the decreasing of the thermodynamic stability of conformers. These interpolation relations allow the calculation of molar fraction of each conformer in the mixture at a certain temperature in the interpolation range of 200-400K. 200 250 300 350 400 -174 -172 -170 -168 -166 -164 -162 -160 -158 -156 -154

A quantitative structure-activity relationships (QSAR) study using Multiple Linear Regression (MLR) and Partial Least Squares (PLS) methodologies was performed for a series of 127 derivatives of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the of the human immunodeficiency virus type 1, HIV-1 reverse transcriptase (RT). The MLR and PLS methods were employed to explore the relationship between the descriptors (as independent variables) of a pool of HEPT derivative and anti-HIV-1 activity, expressed as log (1/EC50) (as dependent variables). Using Dragon descriptors, the present study was aimed at developing a predictive and robust QSAR model for predicting anti-HIV activity of HEPT derivatives for a better understanding of the molecular features of these compounds important for their biological activity. According to the squared correlation coefficients, which had values between 0.826 and 0.809 for the MLR and PLS methods, the results demonstrated almost identical qualities and good predictive ability for both the MLR and PLS models. After dividing the dataset into training and test sets, the model predictability was tested by several parameters, including the Golbraikh-Tropsha external criteria and the goodness of fit, tested using the Y-randomization test.

A QSAR study using Multiple Linear Regression (MLR) and a Partial Least Squares (PLS) methodology was performed for a series of 127 derivatives of 1-(2-hydroxy-ethoxy)methyl]-6-(phenylthio)-timine (HEPT), a potent inhibitor of the of the human immunodeficiency virus type 1, HIV-1 reverse transcriptase (RT). To explore the relationship between a pool of HEPT derivative descriptors (as independent variables) and anti-HIV-1 activity expressed as log (1/EC50), as dependent variable) MLR and PLS methods have been employed. Using Dragon descriptors, the present study aims to develop a predictive and robust QSAR model for predicting anti-HIV activity of the HEPT derivatives for better understanding the molecular features of these compounds important for their biological activity. According to the squared correlation coefficients, which had values between 0.826 and 0.809 for the MLR and PLS methods, the results demonstrate almost identical qualities and good predictive ability for both MLR and PLS models. After dividing the dataset into training and test sets, the model predictability was tested by several parameters, including the Golbraikh-Tropsha external criteria and the goodness of fit tested with the Y-randomization test.

Penicillins are valuable beta-lactam antibiotics and useful starting materials for the preparation of semi-synthetic penicillins and cephalosporins. Penicillins are natural products of fungi such as Penicillium chrysogenum. The theoretical investigation of biological activity of penicillins has been studied systematically in the recent years and provided valuable insights. The diastereoisomer of (3S,5S,6S)-6-acetylamidopenicillanic acid has not yet been investigated. In the current investigation we used FRED (Fast Rigid Exhaustive Docking) to dock the conformers of (3S,5S,6S)-6-acetylamidopenicillanic acid into the crystal structure of Isopenicillin N Acyltransferase in complex with 6-aminopenicillanic acid (PDB code 2X1E). The influence of conformational expansion parameters and energy levels on the docking performances was investigated. The conformers of (3S,5S,6S)-6-acetylamidopenicillanic acid docked into the binding pocket suggested some biological activity on the basis of hydrogen bonding interactions (ARG 310, ASP121 similar to 2X1E ligand, and GLY311) and RMSD values.

A conformational analysis with the semiempirical PM3 method was performed for (3S,5S,6S)-6-acetylamidopenicillanic acid. 105 distinct conformers were found within 25.53 kcal/mol. Dependence of some electronic properties of these conformers (HOMO and LUMO energies, dipole moment, V-min minimum vibration energy, maximum vibration energy V-MAX, zero point vibration energy (ZPVE) and charge densities on atoms S1, N4, N14, O8, O12, O13 and O17) with respect to some geometric characteristics : pseudochirality of the N14 atom, the syn-anti arrangement of the O17 and H28 atoms of the amidic group and the three puckering classes of the thyazolidinic cycle noted with a, b, c, is demonstrated.