Four-Dimensional Structure–Activity Relationship Model to Predict HIV-1 Integrase Strand Transfer Inhibition using LQTA-QSAR Methodology

Abstract

Despite highly active antiretroviral therapy (HAART) implementation, there is a continuous need to search for new anti-HIV agents. HIV-1 integrase (HIV-1 IN) is a recently validated biological target for AIDS therapy. In this work, a four-dimensional quantitative structure-activity relationship (4D-QSAR) study using the new methodology named LQTA-QSAR approach with a training set of 85 HIV-1 IN strand transfer inhibitors (INSTI), containing the β-diketo acid (DKA) substructure, was carried out. The GROMACS molecular dynamic package was used to obtain a conformational ensemble profile (CEP) and LQTA-QSAR was employed to calculate Coulomb and Lennard-Jones potentials and to generate the field descriptors. The partial least-squares (PLS) regression model using 14 field descriptors and 8 latent variables (LV) yielded satisfactory statistics (R2= 0.897, SEC = 0.270, and F = 72.827), good performance in internal (QLOO2 = 0.842 and SEV = 0.314) and external prediction (Rpred2 = 0.839, SEP = 0.384, AREpred = 4.942%, k = 0.981, k′ = 1.016, and |R02 – R0′2 = 0.0257). The QSAR model was shown to be robust (leave-N-out cross validation; average QLNO2 = 0.834) and was not built by chance (y-randomization test; R2 intercept = 0.109; Q2 intercept = -0.398). Fair chemical interpretation of the model could be traced, including descriptors related to interaction with the metallic cofactors and the hydrophobic loop. The model obtained has a good potential for aid in the design of new INSTI, and it is a successful example of application of LQTA-QSAR as an useful tool to be used in computer-aided drug design (CADD).

Benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one derivatives as Aurora A kinase inhibitors: LQTA-QSAR analysis and detailed systematic validation of the developed model

“…The nD-QSAR approaches are good enough to interpret the descriptors into activity prediction models [24,32,[36][37][38].…”

“…In order to have a superior predictive potential of the model, a modified R 2 (R 2 m ) was determined [31]. Further, the model was externally validated by predicting the activity of external set or test set of compounds and evaluated by means of coefficient of determination (R 2 pred ), standard error of external prediction (SEP), and the average relative error (ARE pred ) [32]. Additionally, different external validation techniques were implemented.…”

Development of HIV-1 integrase inhibitors: recent molecular modeling perspectives

“…In addition, Y-randomization is also a good indicator of coincidence rates. De Melo and Ferreira [36] showed that their model (Y-randomization: r 2 intercept = 0.109; q 2 intercept = À0.398) was not built by chance through the Y-randomization test. Applicability domain analysis could further assess the prediction reliability of QSAR models using an extrapolation method [42,43].…”

“…Current IN studies focus on 2D-QSAR and 3D-QSAR, although 4D-QSAR is becoming increasingly popular. De Melo and Ferreira [36] used a 4D-QSAR model to predict IN strand transfer inhibition using Laborató rio de Quimiometria Teó rica e Aplicada (LQTA)-QSAR, which has a module (LQTAgrid) that calculates intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. Further validation showed that this 4D-QSAR model performed well in both internal (q 2 = 0.832, r 2 = 0.905) and external prediction (r 2 pred ¼ 0:839).…”

Integral Sign Change Problem Check in Quantitative Structure-Activity/Property Relationships: A Tutorial

“…As a natural consequence, a simple SCP check 15 was introduced in 2010 to be a tool for rapid SCP detection and elimination, and then extended to a more advanced SCP check 16 in 2012. SCP check has been already applied by some researchers, [20][21][22][23][24] whilst for other QSAR/QSPR groups it served to make them more aware of the danger of SCP. [25][26][27][28] In this work, the previous SCP check 16 is substantially extended to Integral SCP (ISCP) check.…”