Journal of Pharmacy Research Vol.8 Issue 4.April 2014 Subhash Chander et al. / Journal of Pharmacy Research 2014,8(4),552-562 552-562 Research Article ISSN: 0974-6943 Available online through www.jpronline.info * Corresponding author. Sankaranarayanan Murugesan Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani-333031, Rajasthan, India. 1. INTRODUCTION Acquired Immune Deficiency Syndrome (AIDS) is a disease of hu- man immune system caused by Human Immunodeficiency Virus (HIV). According to WHO 2013 report, around 35.3 million people are living with HIV globally. At present, close to 10 million people have access to antiretroviral drugs, but still rest of population awaits these impor- tant medicines for the treatment and prevention of HIV (http:// www.who.int/hiv/en/ cited on 10 Oct. 2013). In the recent decades, the success of anti-HIV drug discovery is certainly related to the fact that the HIV life cycle has been intensely investigated; several of its crucial steps have been validated as drug targets and subsequently many potential inhibitors have been devel- oped against some of these targets. Reverse Transcriptase (RT) is one among the various HIV targets which have been deeply charac- terized and plays major role in viral replication. RT converts the viral single stranded RNA (ssRNA) into proviral double stranded DNA (dsDNA). Consequently this nascent dsDNA, imported into the nucleus of the host cell and integrated into the host genetic material to complete replication cycle. Currently two different classes of HIV In-silico design and docking study of novel Tetrahydroquinoline derivatives as inhibitor of WT and mutant HIV-1 Reverse Transcriptase Subhash Chander, Ashok Penta and Sankaranarayanan Murugesan* Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani-333031, Rajasthan, India. Received on:06-02-2014; Accepted on:08-04-2014 ABSTRACT Background and aim: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are structurally diverse group of compounds which binds to Reverse Transcriptase (RT) enzyme of Human Immunodeficiency Virus (HIV). Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. Therefore, attempts have been made to develop NNRTIs active against both drug sensitive as well as drug resistant strains of HIV-1 RT. Method: Five novel series of Tetrahydroquinoline derivatives were designed as Non-Nucleoside inhibitors of HIV-1 RT based on the pharmacophoric requirements. In-Silico docking studies of the designed analogues were performed against both drug sensitive and resistant strains of HIV-1 RT. Standard drug rilpivirine, etravirine and efavirenz were used for the purpose of docking validation and comparison. Results and discussion: Among the designed analogs, four compounds (2x, 3x, 3f and 5t) showed significant in-silico activity against all three variants of HIV-1 RT. These four compounds were further selected for in-silico prediction of absorption, distribution, metabolism, excretion and toxicity using Quick-pro module of Schrodinger and online tool AdmetSAR respectively. Conclusion: Based on the results of in-silico docking studies and ADMET properties, four compounds (2x, 3x, 3f and 5t) were identified as lead molecules for further development of novel anti-HIV agents active against both wild-type and drug resistant strains with better therapeutic profile. Predicted ADMET properties of these four designed analogues were within the acceptable range of druggable properties. Keywords Docking; HIV; Reverse Transcriptase; Tetrahydroquinoline RT inhibitors available are Nucleoside / Nucleotide Reverse Tran- scriptase Inhibitors (NRTIs/NtRTIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Among these, NNRTIs are play- ing vital role in drug combination therapy called “Highly Active Antiretroviral Therapy” (HAART) which is currently used for HIV treatment. 1 In HAART, combination of three or more anti-HIV drugs (two NRTIs/NtRTIs and one Protease Inhibitor or two NRTIs/NtRTIs and one NNRTI) are used to reduce the emergence of viral resistance and side effects. 2,3 With the advent of HAART, the mortality rate due to AIDS was reduced 60-80% in last one decade and highly fatal AIDS is now become a chronic manageable disease. However, management of this disease is still complex and worrisome due to problems such as development of drug resistance, monitoring of therapy efficacy and poor drug tolerability. Therefore, there is compelling need for the search of novel NNRTIs that possess an improved safety profile, active against both wild and mutant strains of HIV with improved potency and less associated toxic effects. 4 2. Designing of Tetrahydroquinolines as novel HIV-1 RT inhibitor The availability of crystal structures of HIV-1 RT along with co-crys- tallized ligand and the data on drug resistance mutations helped in identifying the factors which can be taken as basis for designing novel inhibitors against both wild and drug resistance strains of HIV- 1. Mutations in NNRTI binding pocket results in the development of drug resistance by either of the following reasons (i) loss or change of key hydrophobic interactions of the inhibitor at the Non-Nucleo-