Docking, molecular dynamics and quantitative structure-activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors

Abstract

As a key component in combination therapy for acquired immunodeficiency syndrome (AIDS), non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been proven to be an essential way in stopping HIV-1 replication. In the present work, in silico studies were conducted on a series of 119 NNRTIs, including 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives by using the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking simulations and molecular dynamics (MD). The statistical results of the optimal model, the ligand-based CoMSIA one (Q(2) = 0.48, R(ncv)(2) =0.847, R(pre)(2) = 0.745) validates its satisfactory predictive capacity both internally and externally. The contour maps, docking and MD results correlate well with each other, drawing conclusions as follows: 1) Compounds with bulky substituents in position-6 of ring A, hydrophobic groups around position- 1, 2, 6 are preferable to the biological activities; 2) Two hydrogen bonds between RT inhibitor and the Tyr 318, Lys 101 residues, respectively, and a π-π bond between the inhibitor and Trp 188 are formed and crucial to the orientation of the active conformation of the molecules; 3) The binding pocket is essentially hydrophobic, which are determined by residues such as Trp 229, Tyr 318, Val 179, Tyr 188 and Val 108, and hydrophobic substituents may bring an improvement to the biological activity; 4) DABO and HEPT derivatives have different structures but take a similar mechanism to inhibit RT. The potency difference between two isomers in HEPTs can be explained by the distinct locations of the 6-naphthylmethyl substituent and the reasons are explained in details. All these results could be employed to alter the structural scaffold in order to develop new HIV-1 RT inhibitors that have an improved biological property. To the best of our knowledge, this is the first report on 3D-QSAR modeling of this series of HEPT and DABO NNRTs. The QSAR model and the information derived, we hope, will be of great help in presenting clear guidelines and accurate activity predictions for newly designed HIV-1 reverse transcriptase (RT) inhibitor.

Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

“…In case of dual inhibitors, the chelating triad of Mg 2+ can be included in pyrimidine core (used an uracil core, [C/N positionX ]): [C p2 ]O-[N p3 ]H(or OH)-[C p4 ]O, where the groups of benzyl or dimethyl-benzyl are bounded in N-1 or C-6 positions [ 20 , 21 , 22 , 118 ]. However, for the actual majority of pyrimidine derivatives NNRTIs inhibitors with an excellent anti-HIV-1 activity of HIV-1 (as HEPT, DABO, DAPY) the following findings are specific [ 21 , 28 , 39 , 40 , 48 , 50 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 89 , 90 , 119 , 120 ]: The position of the molecule is in the hydrophobic region of the NNRTI binding site/hydrophobic interactions (by π–π, π-CH, van der Waals contacts) having as two major substituents of the pyrimidine core the residues Tyr181, Tyr188, Phe227, Trp229, His235, Pro238 and/or Val106; The –CH 2 – linker of benzyl group or methyl group bound to the benzene ring is positioned closely to Glu138 from the p51 domain of RT, while the pyrimidine core is positioned in the area between Leu100 and Val179; The formation of one or more H-bonds with Lys101 (and/or Lys103) where there are possible; The Ar-H interactions with Leu234 are often observed. …”

“…Benzyl groups, with or without –CH 2 – linker modified, are usually involved in hydrophobic interactions, π–π, and/or arenas-H with one or more residues Tyr181, Tyr188, Phe227, Trp229 from NNIBP [ 21 , 28 , 39 , 40 , 48 , 50 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 89 , 90 , 119 , 120 ]. The number and type of these interactions differ more or less from one compound to another, no matter the NNRTI family they belong to.…”

In silico de novo design of novel NNRTIs: a bio-molecular modelling approach

“…Derivatives, belonging to rationally designed broad spectrum NNRTIs, such as dihydroalkyloxybenzyloxopyrimidines (O-DABOs), dihydroalkylthiobenzyloxopyrimidines (S-DABOs), dihydroalkylamino diuorobenzyloxopyrimidines (NH-DABOs), N,N-disubstituted amino(2,6-diuorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones (F2-N,N-DABOs), dihydro-(alkyl thio)(naphthylmethyl)oxopyrimidines (DATNOS), are synthesized. [47][48][49][50][51][52] The present study deals with design of novel NNRTIs by performing chemometric analyses of two important types of descriptors namely (a) 3D pharmacophoric [dipole moment, S ALL , HD ALL , R ALL and HA ALL ] and (b) 2D average alignment [octanol-water partition coefficient (C log P) descriptors in understanding the interactions potential of 5-alkyl-2-alkylamino-6-(2,6-diuorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-one (DABO) analogs in the NNIBP. The three substituents R and X are attached to the pyrimidinone ring while R 0 is attached to the bridging CH group.…”

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis, Molecular Modeling Studies, and Identification as Stereoselective Inhibitors of HIV‐1

“…Crystallographic analysis of the HIV‐1 RT–NNRTI complex of the first‐generation NNRTIs such as nevirapine and delavirdine has revealed a common “butterfly‐like” conformation despite the chemical diversity between these compounds 5, 6. By contrast, diarylpyrimidine (DAPY) analogues such as etravirine and rilpivirine, belonging to the third generation NNRTIs, adopt different conformational modes popularly called “giggle and wiggle” through their torsional flexibility and ability to reposition within the NNRTI binding pocket 1, 7, 8.…”