Articles

Recently, we have studied drug-receptor interaction of the peptidic HIV-1 protease inhibitors based on polar and hydrophobic interactions. We have also studied pharmacokinetics of these inhibitors based on Lipinski’s rule of five and its extended form. After that there was a need to study intermolecular interactions. From literatures, drug-receptor interaction involves hydrogen bonds between acceptor and donor sites of drug and its receptor. These donor acceptor sites must be more than four to be dominant. As single intermolecular H-bond is relatively weak and unlikely to support this type of interaction. It is also clear from literature that this interaction contribute to the alignment of reacting species in proper three-dimensional space in such a position that strong and effective polar or hydrophobic or both interaction occurs to form drug-receptor adduct or enzyme inhibitor complex as appropriate. The strength of H-bonds formed between drug and receptor was judged by bond lengths, bond angles and bond orders. As well as, its nature (strong, moderate or weak) and its number, too. Along with H-bonding, we have also studied Van der Walls i.e. non-bonding type interaction. These non-bonding interactions were studied using charge transfer from donor to acceptor and this results transfer of electron flux from donor molecule (drug/receptor) towards acceptor (receptor/ drug). Thus, lowering of energy of the system under investigation will occur. For this resulted interaction energy was also studied that very clearly explain feasibility of interactions. As we know that all above phenomena are molecular properties and do not cover involvement of orbitals. To cover this we have also studied drug-receptor interaction involving molecular orbital. It was HOMO of one reacting molecule (B) that donates electron pair, electron cloud or electron density to LUMO of another reacting molecule (A) that accepts or accommodates this electron pair, electron cloud or electron density. The quantity of the electron flux from HOMO to LUMO was judged by the value of ∆E_LH. A lower value of this will support strong and effective drug-receptor interaction. Results of orbital based study have also been found to supports the results as abstracted from interaction energy.

Klopman described the chemical reaction of metal ions and base ions in term of softness, E^‡_n and E^‡_m, respectively. By simple modification of known methods, Singh et al. made it applicable for neutral Lewis acids (transition metal salts) and bases (organic molecules) and also extended its application to biological systems for site selectivity and to explain reaction mechanism (markovnikov and anti-markovnikov rule), ligand-receptor interaction of testosterones, estrogens and tetrahydroimidazobenzodiazepinone. In this study effective atomic softness E^‡_n(eff) and E^‡_m(eff), and their change ΔE^‡_nm have been used for site selectivity and polar interaction between 51 peptidic HIV-1 protease inhibitors and receptor amino acids. ΔE^‡_nm values derived from drug-receptor interaction show that when one moiety on receptor behaves as nucleophile (O of valine amino acid) at the same time maximum electrophilic site of the drug (C-atom of the maximum E^‡_n(eff) value) orient itself to come close the respective site and make maximum interaction, while when another moiety on receptor behaves as electrophilic site (C of isoleucine amino acid), at the same time maximum nucleophilic site of the drug (O-atom of the maximum E^‡_m(eff) value) also orient itself to come close the respective site and make maximum interaction.

In this research work, we have applied “Lipinski’s RO5” for pharmacokinetics (PK) study and to predict the activity of peptidic HIV-1 protease inhibitors. Peptidic HIV-1-PRIs have been taken from literature with their observed biological activities (OBAs) in term of IC50. The logarithms of the inverse of IC50 have been used as biological end point o(log1/C) in the study. For calculation of physicochemical parameters, the molecular modeling and geometry optimization of all the derivatives have been carried out with CAChe Pro software using semiempirical PM3 method. Prediction of the biological activity of the inhibitors has shown that the best QSAR model is constructed from pharmacokinetic properties, molecular weight and hydrogen bond acceptor. This also proved that these properties play important role to describe the PKs of the drugs. On the basis of the derived models one can build up a theoretical basis to access the biological activity of the compounds of the same series.