ORIGINAL RESEARCH Molecular docking, QPLD, and ADME prediction studies on HIV-1 integrase leads Sunil Kumar Tripathi • Chandrabose Selvaraj • Sanjeev Kumar Singh • Karnati Konda Reddy Received: 20 July 2011 / Accepted: 9 December 2011 / Published online: 8 January 2012 Ó Springer Science+Business Media, LLC 2012 Abstract HIV-1 integrase (IN) is an important drug tar- get over the years with diverse therapeutic potential with the objective of designing new chemical entities with enhanced inhibitory potencies against HIV-1 IN. We per- formed molecular docking, quantum polarized ligand docking (QPLD), ADME screening, and PASS biological activity prediction studies on Raltegravir, Elvitegravir, and newly searched compounds of Cambridge crystallographic database. Best docking and QPLD scores of known and unknown searched compounds were compared using docking score, docking energy, and emodel energy. Moreover, correlation between docking score, docking energy with emodel energy yielded a statistically signifi- cant correlation coefficient. The searched compounds were also evaluated with ADME properties and biological activity prediction analysis. These compounds also show good pharmacokinetic properties under the acceptable range including antiviral biological activity prediction. Hence, these compounds could be employed to design ligands with enhanced inhibitory potencies and to predict the potencies of analogs to guide synthesis/or prepare synthetic analogs for second generation drug development against HIV-1 IN. Keywords HIV-1 integrase  Docking  ADME  QM/MM  QPLD  CSD Introduction Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). The highly active antiret- roviral therapy (HAART) includes inhibitors that target viral entry, and the viral enzymes reverse transcriptase (RT) and protease (PR). These inhibitors are prone to drug resistance, as a consequence of the high mutation rate of HIV-1 that leads to extensive natural polymorphism, and as a result the design of novel high genetic barrier inhibitors remains a challenge. The integration of viral DNA into the human chromosome, catalyzed by HIV-1 integrase (IN), is an essential step for the survival of HIV and a viable target for antiviral agents (Eriketi et al., 2009). The copy of the HIV genome in DNA form is inserted into the host’s genome by the enzymatic action of IN (Pommier et al., 2005; Thomas and Brady, 1997). The IN protein has three domains, namely, the N-terminal domain stabilized by Zn 2? , the DNA binding C-terminal domain (Lee and Han, 1996; Zheng et al., 1996; Lee et al., 1997; Khan et al., 1991). The structure of the C-terminal and N-terminal domains of the IN were solved by NMR, whereas, the catalytic domain of IN was determined by X-ray crystal- lography (Lodi et al., 1995; Cai et al., 1997; Eijkelenboom et al., 1995; Dyda et al., 1994; Bujacz et al., 1995). A number of natural products inhibiting IN have been reported recently (Deng et al., 2005). Three unique and essential HIV enzymes, PR, RT, and IN, appear to be ideal targets for the development of inhibitors of HIV replica- tion. Anti-HIV drugs targeting PR [PR inhibitors (PIs)] and RT [nucleoside/nucleotide RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs)] have been approved for use in the treatment of HIV infection. Com- bination of these drugs used in HAART can effectively S. K. Tripathi  C. Selvaraj  S. K. Singh (&)  K. K. Reddy Computer-Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu 630002, India e-mail: skysanjeev@gmail.com 123 Med Chem Res (2012) 21:4239–4251 DOI 10.1007/s00044-011-9940-6 MEDICINAL CHEMISTRY RESEARCH