ORIGINAL RESEARCH Structure-based virtual screening and docking studies for the identification of novel inhibitors against wild and drug resistance strains of HIV-1 RT Subhash Chander • Ashok Penta • Sankaranarayanan Murugesan Received: 5 July 2014 / Accepted: 8 September 2014 / Published online: 24 September 2014 Ó Springer Science+Business Media New York 2014 Abstract 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 discover the NNRTIs active against both drug sensitive, as well as drug resistant strains of HIV-1 RT. In the present study, using structure-based virtual screening online data- base of small molecules was screened against wild strain of HIV-1 RT. Among the screened ligands, top thirty hits which exhibited lowest G score against wild HIV RT were further evaluated against two clinically drug resistance strains of HIV-1 RT. Docking study of these top thirty hits revealed that around nine ligands exhibited significant binding affinity (G score less than -10) against wild, as well as two drug resistance strains of HIV-1 RT. These nine compounds were further selected for in silico pre- diction of physiochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters using QikProp module of Schro ¨dinger and online tool admetSAR. Keywords Virtual screening Á Docking Á Maybridge Á HIV Á Reverse transcriptase Á Mutation Introduction In the recent two 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 developed against some of these targets (Ballana and Este, 2013). Reverse transcriptase (RT) is one among the various HIV targets which have been deeply characterized and plays major role in viral replication. RT converts the viral single-stranded RNA into proviral double stranded DNA (Sarafianos et al., 2004). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are playing vital role in drug combination therapy called ‘‘Highly Active Antiretroviral Therapy’’ (HAART) which is currently used for HIV treatment (Kozal, 2009). In current therapy (HAART), combination of three or more anti-HIV drugs are used in order to reduce the emergence of viral resistance, its preferred combina- tions are two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) with one protease inhibitor alternatively two NRTIs/NtRTIs with one NNRTI. (Brechtl et al., 2001; Sun et al., 2012). Compared to NRTIs, NNRTIs have the advantage of high potency, low toxicity, high selectivity, and specificity (Bell et al., 1995). In last one decade, after the advent of HAART, the mortality rate due to AIDS was reduced 60–80 % 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 (Chong et al., 2012). Therefore, there is compelling need for the search of novel NNRTIs that possess an improved safety profile, active against both wild and drug resistance strains of HIV with improved potency and less associated S. Chander Á A. Penta Á S. Murugesan (&) Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India e-mail: murugesan@pilani.bits-pilani.ac.in S. Chander e-mail: subhashsaininiper@gmail.com 123 Med Chem Res (2015) 24:1869–1883 DOI 10.1007/s00044-014-1251-2 MEDICINAL CHEMISTR Y RESEARCH