Vol 7, Issue 5, 2014 ISSN - 0974-2441 MOLECULAR DOCKING STUDIES AND ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION PREDICTION OF NOVEL ISATIN ANALOGS AS HUMAN IMMUNODEFICIENCY VIRUSǧ1ǧREVERSE TRANSCRIPTASE INHIBITORS WITH BROAD SPECTRUM CHEMOTHERAPEUTIC PROPERTIES BIPLAB DEBNATH*, SWASTIKA GANGULY Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi - 835 215, Jharkhand, India. Email: biplab.d86@gmail.com Received: 26 August 2014, Revised and Accepted: 13 September 2014 ABSTRACT Molecular docking studies were performed on 100 newly designed isatin analogs using Glide v 5.0 on the active site of four different enzymes namely human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) protein data bank (PDB ID 1RT2), glucosamine 6-phosphate (GlcN6P) (PDB ID 2VF5), Mycobacterium tuberculosis-CYP51 (PDB code 1EA1) and Candida albicans (CACYP51) (PDB code chimeric-1EA1) to study the binding mode of these analogs to study the binding mode of these analogs. Binding mode analysis of the compounds with the highest docking scores (−11.67, −7.31, −7.12 and −8.54) were carried out and compared with that of the co crystallized ligands TNK651, glucosamine (glucagon-like peptide) and fluconazole (TPF) in the active sites of 1RT2, 2VF5,1EA1, and chimeric 1EA1 respectively. Absorption, distribution, metabolism and excretion (ADME) properties of all the newly designed isatin analogs 1-100 was calculated by QikProp v 3.0. All the designed compounds were found to exhibit lead like properties from the calculated ADME properties. Results of these docking analyses can be well used for the design and development of novel isatin analogs possessing HIV-1-RT inhibitory activity with broad spectrum chemotherapeutic properties. Keywords: Isatin analogs, Docking, Human immunodeficiency virus, Non-nucleoside reverse transcriptase inhibitors, Non-nucleoside inhibitory binding pocket, Lipinski’s rule and absorption, distribution, metabolism and excretion. INTRODUCTION Acquired immune deficiency syndrome (AIDS) is one of the most vital challenges to public health care systems worldwide [1]. It is caused by human immunodeficiency virus (HIV), which belongs to the lent virus subfamily [2,3]. There are about 33 million people living with HIV/AIDS [4], whereas 25 million AIDS-related deaths have been reported in the last 25 years [5]. After so many years of its discovery, HIV is still a major health and socio-economic issue, specifically in developing countries [6]. During acute HIV infection, the virus directly infects CCR 5 -expressing CD4 + Tcells, leading to their rapid depletion [7]. This result in a wide range of irreversible HIV-associated immunologic dysfunction or opportunistic infections like bacterial and fungal diseases, tuberculosis (TB), cancers, neurologic symptoms and wasting syndromes as well as it causes immunodeficiency [8]. Two main categories of HIV-reverse transcriptase (RT) inhibitors have been discovered to date. The first category of inhibitors is the nucleoside/nucleotide RT inhibitors (NRTIs), which bind to the enzymatic site of RT in a competitive manner with natural nucleotides and thereby terminates DNA synthesis after their incorporation into the growing DNA chain. The second groups of inhibitors are the non-NRTIs (NNRTIs), a group of structurally and chemically different compounds that non-competitively and selectively bind to the unique allosteric hydrophobic non-nucleoside inhibitory binding pocket (NNIBP) causing non-competitive inhibition of the viral polymerase [9]. TB is accountable for severe morbidity and mortality, mainly in developing countries where control interventions are remote, excessive and plagued by well-known drug resistance. It is caused by the intracellular pathogens Mycobacterium sp. It naturally affects the lungs (pulmonary TB), but can affect other organs as well as it can cause extra pulmonary TB. In 2010, there were an estimated 8.8 million new cases of Mycobacterium tuberculosis (MTB) and 1.5 million associated deaths, mostly occurring in developing countries. In India, one person dies of TB every minute [10,11] and India had the largest total incidence, with an estimated 2.0 million new cases [12]. Currently, TB is becoming a worldwide problem and it was declared since 1993 a global health emergency by the World Health Organization, the renaissance of TB became a serious world-wide problem during the period 1985-1992, particularly in people infected with the HIV. One of the major concerns is that it is the most common HIV-related opportunistic infection, thus treatment of the patients infected with both the diseases is a major challenge [13-15]. More than half a million people die from HIV-associated TB annually [16]. Lethal combination of TB and HIV infection for nearly the past three decades has posed a major threat to the international community’s effort to achieve the health-related United Nations Millennium Development Goals for TB and HIV infection [17]. In addition to that, the emergence of drug-resistant strains of MTB has led to an enlarged pressure on present chemotherapy regimens. Microbial infections have always been a growing problem in contemporary medicine, and the uses of antimicrobials are common across the world. Antimicrobials are, therefore, essential treatments, especially in the developing world where infectious diseases are a common cause of death. The rapid prevalence of the AIDS epidemic, as well as an increase in the use of immunosuppressant’s, has also resulted in an abnormal increase in the incidence of systemic microbial infections. Antibiotics are among the most commonly used drugs, which are misused by physicians. The inevitable consequence of widespread and injudicious use of antibiotics has been the emergence of antibiotic-resistant pathogens, resulting in a serious threat to global public health [18]. This increase in resistance against the current day antibiotics demands to explore and synthesize a novel class of antimicrobial compounds effective against pathogenic microorganisms that have developed resistance to the antimicrobials used in the current regimen [19,20]. In recent years, due to the overzealous use of antibacterial antibiotics, the use of immunosuppressive agents, cytotoxins, irradiation and steroids, a new category of systemic mycoses has become prominent. Research Article