HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors Research Articles

Synthesis and molecular docking studies of quinoline derivatives as HIV non-nucleoside reverse transcriptase inhibitors.

Quinoline moiety is an important scaffold in the field of drug discovery and drug development, with a wide range of pharmacological activities. Quinoline derivatives are potent inhibitors for reverse transcriptase, which is responsible for the conversion of single-stranded viral RNA into double-stranded viral DNA.In the present study, we have designed and synthesized 2 series, namely pyrazoline and pyrimidine containing quinoline derivatives as non nucleoside reverse transcriptase inhibitors (NNRTIs). Eleven compounds were synthesized and characterized by 1H and 13C NMR and mass spectrophotometry. The synthesized compounds were also docked on an HIV reverse transcriptase binding site (PDB: 4I2P); most of these compounds showed good binding interactions with the active domain of the receptor. Most of the compounds displayed a docking score higher than those of standard drugs. Among the synthesized quinoline derivatives, compound 4 exhibited the highest docking score (–10.675).

Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC50 values ranging from 2.45nM to 5.36nM, and 14c (EC50=2.45nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC50=10.6nM), being comparable with ETR (EC50=9.80nM) and 3.5-fold more potent than that of compound 7 (EC50=37.3nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50=0.0589μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.

Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties.

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50=0.0021μM), 1.7-fold (K103N, EC50=0.0019μM), and slightly more potent (E138K, EC50=0.0075μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50=18.52μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3 (Fraction of sp3 carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.

Computational Studies of 3D-QSAR on a Highly Active Series of Naturally Occurring Nonnucleoside Inhibitors of HIV-1 RT (NNRTI)

HIV is one of the deadliest viruses in the history of mankind, it is the root cause of Acquired Immunodeficiency Syndrome (AIDS) around the world. Despite the fact that the antiviral therapy used against HIV-1 infection is effective, there is also rapidly growing cases of drug resistance in the infected patient along with different severe side effects. Therefore, it is of dire and immediate need to find novel inhibitors against HIV-1 Reverse Transcriptase (RT). In this study, the potential of naturally occurring compounds extracted from plants has been studied with the help of Three-Dimensional-Quantitative Structure–Activity Relationships (3D-QSAR) analysis. A total of 20 compounds, retrieved from a ZINC database, were analyzed with the help of 3D-QSAR to identify a potential inhibitor of HIV-1 RT. By evaluation of seven models generated with the help of MIF analysis and 3D-QSAR modeling, compound 3 (ZINC ID: ZINC20759448) was observed to outperform others by showing optimal results in QSAR studies. This compound has also been biologically validated by a recently reported previous study. Thus, this compound can be used as a potential drug against infection caused by HIV-1, specifically AIDS.

Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures, a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3H)-ones were designed, synthesized and evaluated for their antiviral activities in MT-4 cells. Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC50 values ranging from 7.55 μmol/L to 0.018 μmol/L. Among them, compound 5c was identified as the most promising inhibitor against HIV-1 replication with an IC50 = 0.018 μmol/L, CC50 = 194 μmol/L, and SI = 12791, which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV. In addition, 5c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02. The preliminary structure-activity relationship (SAR) and molecular modeling studies were also discussed, which provides some useful indications for guiding the further rational design of new S-DACO analogues.

Computational Studies of 3D-QSAR on a Highly Active Series of Naturally Occurring Non-Nucleoside Inhibitors of HIV-1 RT (NNRTI)

Computational Studies of 3D-QSAR on a Highly Active Series of Naturally Occurring Non-Nucleoside Inhibitors of HIV-1 RT (NNRTI)

Uracil-Containing Heterodimers of a New Type: Synthesis and Study of Their Anti-Viral Properties.

Widespread latent herpes viral infections within a population can lead to the development of co-infections in HIV-infected patients. These infections are not particularly dangerous for healthy individuals and often occur with minimal symptoms, but for those who are immunocompromised, these infections can accelerate the acute phase of HIV infection and AIDS. Thus, the idea of designing compounds that could combine activity against HIV and co-infections would seem promising. In that regard, eleven compounds were synthesized that represent conjugates of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside inhibitors of the herpes family viruses with the hope that these novel heterodimers will result in dual activity against HIV and concomitant herpes virus infections.

Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors

The single enantiomers of seven hydroxyl-substituted biphenyl-diarylpyrimidines were designed and synthesized by a bioisosterism strategy as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The cellular and enzymatic assays indicated that the novel obtained compounds had significant activities and relatively low cytotoxicity. The supercritical fluid chromatography (SFC) enantioseparations of the racemic compounds and the enantiomeric profiling resulted that the (S) forms were generally more potent than the (R) counterparts. Among all the chiral derivatives, (S)-(−)-12a showed the best potency with the antiviral activities against wild-type (WT) and single mutant strains (L100I, K103 N, Y181C, E138K; especially Y188L), and RT enzyme in the low nanomolar concentration range. Toward double mutant virus strains (F227L + V106A, RES056), (S)-(−)-12a possessed submicromolar antiviral activities. In addition, (S)-(−)-12a showed a high cell-based selectivity index (SI WT = 5822) and no apparent toxicity was observed in the in vivo acute toxicity assay and electrocardiogram. The molecular docking studies predicted the binding modes of the compounds with RT and explained the activity differences for the enantiomers. Although the rat pharmacokinetic assay indicated a poor oral metabolism of the hydroxyl compound, the promising antiviral activity of the chiral hydroxyl-substituted biphenyl-diarylpyrimidines provided valuable lead compounds for further anti-HIV drug design.

Insights into Biophysical Methods to Study Interactions Between HIV-1 Reverse Transcriptase and Non-nucleoside Reverse Transcriptase Inhibitors

Background:Reverse Transcriptase (RT) of immunodeficiency virus type-1 (HIV-1) remains an essential target for new antiretroviral therapies. Non-nucleoside reverse transcriptase inhibitors (or NNRTIs) constitute a major class of RT inhibitors whose characterization is essential.Introduction:Several biochemical, biological, and biophysical methods have been previously used to analyze the biological effects of NNRTIs. We explored here the use of surface plasmonic resonance to characterize the affinity of RT towards selected NNRTIs and compared the results with those obtained with in vitro and in cellulo assays.Methods:The solubility and stability in buffers of the tested NNRTIs were assessed by spectrophotometry and fluorescence. Surface plasmonic resonance experiments to study direct NNRTIs binding to immobilized RT and intramolecular quenching of RT tryptophan fluorescence were used to determine the KA association constants (= 1/KD) between RT and the inhibitors. The in vitro inhibition constants of RT were determined using kinetics and the effects on three other potential targets (proteasome, HIV-1 integrase, and HIV-1 protease) were analyzed.Results:The results obtained with two typical molecules belonging to our previous N-hydroxyureido acylnucleoside derivatives series using the above biophysical assays matched those obtained in in vitro and previous in cellulo assays.Conclusion:Surface plasmonic resonance provides reliable thermodynamic information on the interaction of RT with NNRTIs and appears as a useful method for understanding their inhibitory mechanism.

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines.

A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic in silico study was performed on 52 DHPYs using three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q2, R2, and of the optimal comparative molecular similarity indices analysis model were 0.647, 0.970, and 0.751, respectively. The docking results indicated that residues Lys101, Tyr181, Tyr188, Trp229, and Phe227 played important roles for the DHPY binding. Nine lead compounds were obtained by the virtual screening based on the docking and pharmacophore model, and three new compounds with higher docking scores and better ADME properties were subsequently designed based on the screening and 3D-QSAR results. The MD simulation studies further demonstrated that the newly designed compounds could stably bind with the HIV-1 RT. These hit compounds were supposed to be novel potential anti-HIV-1 inhibitors, and these findings could provide significant information for designing and developing novel HIV-1 NNRTIs.

Binding interaction of potent HIV-1 NNRTIs, amino-oxy-diarylquinoline with the transport protein using spectroscopic and molecular docking.

In the present investigation, the intermolecular interaction of 4-(4'-cyanophenoxy)-2-(4''-cyanophenyl)-aminoquinoline (1), a potent non-nucleoside HIV-1 reverse transcriptase inhibitors, with the transport proteins, namely bovine serum albumin (BSA) and human serum albumin (HSA), has been investigated under physiological conditions employing UV-Vis, fluorescence spectrophotometry, competitive binding experiments and molecular docking methods. The results indicated that binding of (1) to the transport proteins caused fluorescence quenching though a static quenching mechanism. The number of binding site (n) and the apparent binding constant (Kb) between (1) and the transport proteins were determined to be about 1 and 104-105L·mol-1 (at three different temperatures; 298, 308, 318K), respectively. The interaction of (1) upon binding to the transport proteins was spontaneous. The enthalpic change (ΔH°) and the entropic change (ΔS°) were calculated to be -56.50kJ·mol-1, -72.31J·mol-1K-1 for (1)/BSA, respectively and computed to be -49.35kJ·mol-1, -58.64J·mol-1K-1, respectively for (1)/HSA, respectively. The results implied that the process of interaction force of (1) with the transport protein were Vander Waals force and/or hydrogen bonding interactions. The site maker competitive experiments revealed that the binding site of (1) with the transport proteins were mainly located within site I (sub-domain IIA) in both proteins. Additionally, the molecular docking experiment supported the above results which confirmed the binding interaction between (1) and the transport proteins. This study will come up with basic data for explicating the binding mechanisms of (1) with the transport protein and can be great significance in the opening to clarify the transport process of (1) in vivo.

Synthesis, molecular docking and biological evaluation of 2-(thiophen-2-yl)-1H-indoles as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

New 2-(thiophen-2-yl)-1H-indole derivatives bearing hydrophobic substituents at the 3-position were designed, synthesized and evaluated for their inhibition of HIV-1 reverse transcriptase (RT) enzyme. Dialkylphosphites (2a-c) or trialkylphosphites (3a-c) were reacted with 2-(thiophen-2-yl)-1H-indole-3-carbaldehyde (1) yielding the corresponding α-hydroxyphosphonate adducts (7a-7c). The reaction of compound 1 with the ylidenetriphenylphosphoranes (4a-4c) proceeds via Wittig mechanism giving the corresponding ethylenes (E, 8a-c). Compounds 8b,c were equally obtained upon reacting aldehyde 1 with the appropriate dialkylphosphonates 5a,b under the Horner-Wittig reaction conditions. On the other hand, the reaction of aldehyde 1 with diethyl cyanomethylene phosphonate (5c) yielded a mixture of the E-ethylene 10 and the cyanovinyl phosphonate 11. The thioaldehyde 12 was obtained upon refluxing aldehyde 1 with the Lawesson's reagent (LR, 6a) or with the Japanese reagent (JR, 6b) in dry toluene. Upon evaluation of HIV-1 Reverse Transcriptase enzyme inhibition, compound 8b (IC50=2.93nM) exhibited the superior HIV-1 RT inhibition and its potency was about 3-folds that of Efavirenz (IC50=6.03nM). Also, compounds 9a (IC50=4.09nM) and 12 (IC50=3.54nM) showed significantly higher inhibition potency. Moreover, compounds 7b (IC50=7.48nM), and 8a (IC50=4.55nM) showed potency not significantly different from that of Efavirenz. Molecular docking experiments on these potent compounds was in accordance with the in vitro data and confirmed binding of these compounds to the enzyme through ring-stacking and hydrogen bond interactions. According to these results, the new molecules would serve as potent HIV-1 NNRTIs inhibitors.

Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors.

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.

Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure–activity relationship and PK profiles were also discussed.

Rational Design of Doravirine: From Bench to Patients.

Since the approval of nevirapine, the first HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) in 1996, NNRTIs have helped play a critical role in maintaining viral suppression in people living with HIV. The many positive attributes of the class, including potency and long plasma half-life, make them attractive drug discovery targets. Given the availability of multiple once-daily integrase-based treatments for HIV-1 infection, the challenge to develop a new antiretroviral agent that addresses the needs of today's patients is formidable. However, with the increased availability of antiretrovirals for treatment and new pre-exposure prophylaxis guidelines, which should globally expand the use of antiretrovirals in prevention, it will be increasingly important to have access to multiple regimens with options from different classes that are well tolerated and convenient to ensure a sustained impact on the global epidemic. Many attempts to improve upon the NNRTI class have failed to deliver a desirable clinical profile consistent with the current landscape of treatment options. Doravirine is the only NNRTI to successfully advance through phase 3 clinical development and approval in recent years. Learning from the liabilities of approved NNRTIs, as well as past development failures, facilitated a rational approach to the discovery of doravirine by focusing on addressing the known safety/tolerability issues of commonly prescribed NNRTIs, such as central nervous system toxicity with efavirenz and potential cardiotoxicity due to off-target effects on cardiac ion channels with rilpivirine, using structural biology and characterization of resistance in vitro to address resistance liabilities and concentrating on the metabolic profile to limit the potential for drug-drug interactions. These preclinical efforts were critical to the design and selection of doravirine as a novel NNRTI that possessed the desired next-generation profile with the ultimate proof that these attributes translate to patients derived from clinical trials.

Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles.

Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.

Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs

In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure–activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

New strategy for identifying potential natural HIV-1 non-nucleoside reverse transcriptase inhibitors against drug-resistance: an in silico study

Non-nucleosides reverse transcriptase inhibitors (NNRTIs), specifically targeting the HIV-1 reverse transcriptase (RT), play a unique role in anti-AIDS agents due to their high antiviral potency, structural diversity, and low toxicity in antiretroviral combination therapies used to treat HIV. However, due to the emergence of new drug-resistant strains, the development of novel NNRTIs with adequate potency, improved resistance profiles and less toxicity is highly required. In this work, a novel virtual screening strategy combined with structure-based drug design was proposed to discover the potential inhibitors against drug-resistant HIV strains. Seven structure-variant RTs, ranging from the wild type to a hypothetical multi-mutant were regarded as target proteins to perform structure-based virtual screening. Totally 23 small molecules with good binding affinity were identified from the Traditional Chinese Medicine database (TCM) as potential NNRTIs candidates. Among these hits, (+)-Hinokinin has confirmed anti-HIV activity, and some hits are structurally identical with anti-HIV compounds. Almost all these hits are consistent with external experimental results. Molecular simulations analysis revealed that top 2 hits (Pallidisetin A and Pallidisetin B) bind stably and in high affinity to HIV-RT, which are ready to be experimental confirmed. These results suggested that the strategy we proposed is feasible, trustworthy and effective. Our finding might be helpful in the identification of novel NNRTIs against drug-resistant, and also provide a new clue for the discovery of HIV drugs in natural products.Communicated by Ramaswamy H. Sarma.

3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2′-fluoro and 3′-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2′-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 μM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.