Pharmacophore Modelling and 4D QSAR Analysis of Some Indole Glyoxamide Derivatives as HIV-1 Binding Inhibitors

Abstract

The main aim of this study is to uncover the main pharmacophoric features of a series of indole glyoxamide derivatives which are known as HIV-1 attachment inhibitors and to estimate the biological activity to develop a 4D-QSAR model by using the EC-GA method. Conformational analysis and quantum mechanical calculations were accomplished by using the Hartree Fock method with the 3-21G basis set. Based on the data produced from the quantum chemical calculations, the electron conformational matrices of congruity (ECMC)s, as the 3D- arrangement of electronic and geometric properties, were generated by the EMRE program. An individual ECMC was formed for each conformer of each indole glyoxamide derivative in the data set. Conformational flexibility was considered for each compound. Totally 1510 ECMCs were produced by EMRE software to be used in the comparison process. By analogizing the ECMCs in a predetermined tolerance value, the subset of common features matching all active compounds but not matching the low activity compounds was determined. The final ECSA was obtained as a set of nine atoms including predominantly hydrogen bond donors, hydrogen bond acceptors and lipophilic units. Key elements are mainly placed in indole nitrogen, carbonyl groups and piperazine ring. In the bioactivity prediction and variable selection, the genetic algorithm and non-linear least square techniques were employed. The obtained models were internally and externally validated by the leave-one-out cross-validation method. The resulting 4D QSAR EC-GA models were compared with the other methods and the best model with the high prediction ability was defined according to R2training=, R2test =0.8 cross-validatedated q2 =0.860, q2ext1 = 0.850 and q2ext1 = 0.850 values. Attained EC-GA model provides insight into the vital interaction between indole glyoxamide derivatives and the target protein. EC-GA models can be utilized as an effective and confidential tool in the design of more potent indole glyoxamide derivatives.