Current Topics in Medicinal Chemistry - Volume 14, Issue 17, 2014

The role of the medicinal chemistry in drug discovery industry has undergone major changes in the past two decades, due to the development of new technologies such as combinatorial chemistry, computational biology and chemisty [1-3]. Over the years, tremendous research has carried out towards the designing new chemical entities for various therapeutic areas using recent technologies such as combinatorial chemistry and virtual screening approaches. In current issue of “Current Topics in Medicinal Chemistry (CTMC)”, we focused on the literature review on potential therapeutic targets, and virtual screening strategies towards the design and discovery of new chemical entities in entitled the special topic with “Medicinal chemistry update and discovery strategies on potential therapeutic targets”. Articles in this special issue have been contributed by experts from many parts of the world. In first article, Drs. Rahul and Se Won Park covered extensive step-by-step summary of anti-HIV breakthroughs of triterpene acid analogues and their derivatives with synthetic and activity aspects, featuring fertile clues for novel anti-HIV drug design, which helps to develop unprecedented opportunities to discover the next-generation anti-HIV armamentarium. In second article, Drs. Riyaz and Ahmed Kamal has covered a brief review on tankyrase inhibitors and its structure activity relationships (SAR). In the next article, Drs. Siddharth Malik & Suneel has covered list of small molecule inhibitors targeting anthrax lethal factor activity and its structure-activity relationships (SAR). In the another article, Drs. Shalini & Sriram has discussed about most of potent series of DNA gyrase inhibitors & its structure activity relationships (SAR). The current manuscript also reports the current research on identification of potent DNA gyrase inhibitors using ligand based virtual screening approaches. In next article, Drs. Raghu & Vijaya Lakshmi has covered an overview to the available crystal complexes of Aurora Kinases and their co-crystal interactions and also quantified with glide-extra precision (XP) docking. Also covers identification of potential leads against aurora kinase using various rational methods of drug discovery. In the next article, Drs. Singh & Sarma has describes an overview on clinical candidates of PARP1 and its current status in clinical trials and also discussed about recent study on identification of potent PARP1 inhibitors using structure and ligand based pharmacophore models. In the last article, Drs. Suneel & Sarma has discussed about recent study on identification of potent FGFR1 inhibitors using ligand based virtual screening approach.

HIV infection/AIDS, is a fatal disease multiplying rapidly in virtually every country. Extensive creations are in progress to arrest the replication of the HIV, following the destruction of either particular step involved in the progression of HIV infection. In such endeavors, mechanistically more diverse antiviral therapies were showcased using naturally occurring triterpene acid and their derivatives acting at various stages of HIV life cycle like entry or fusion, function of HIV protease enzyme and finally at maturation. The present article holds an extensive step-by-step summary of anti-HIV breakthroughs of triterpene acid analogues and their derivatives with synthetic and activity aspects, featuring fertile clues for novel anti-HIV drug design, which helps to develop unprecedented opportunities to discover the next-generation anti- HIV armamentarium.

Tankyrase 1 and 2 belonging to the family of poly(ADP-ribosyl)ases play an important role in PARsylation by utilizing NAD+ as a substrate in order to generate ADP-ribose polymers. Tankyrases are involved in a number of cellular functions, that includes telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt/β-catenin signalling, and viral replication. These roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified as potential clinical leads. The current review covers the progress, mechanism and binding modes of recently known Tankyrase inhibitors and discusses the rational approaches that were used to identify the tankyrase inhibitors.

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).

Among the topoisomerases, DNA gyrase belongs to the type II classes that catalysing DNA supercoiling or relaxation, catenation or decatenation, knotting or unknotting. It is one of the validated targets for anti-tubercular drug discovery and inhibitors from this group are also active against non-replicating, persistent mycobacteria, which might be important for shortening the duration of TB therapy. From past few years, extensive research was carried out towards potent DNA gyrase inhibitor design. The current review focuses on the most of potent series of DNA gyrase inhibitors and its structure activity relationships (SAR). The current manuscript also reports the current research on identification of potent DNA gyrase inhibitors using ligand based virtual screening approaches. The pharmacophore model was developed and validated against 65 known Mycobacterium smegmatics (MS) DNA Gyrase inhibitors. Validated pharmacophore model consists of HBA, HY, and RA features were essential for DNA Gyrase inhibition and this model was used to screen virtual screening to retrieve potential inhibitors from our in house database. Finally, 15 hits were ranked as potential leads based on pharmacophoric fit value and estimated activity. Furthermore, in-vitro enzymatic inhibition studies were performed for these 15 most promising candidates and these compounds were found to exhibit inhibition at 30µM.

Cancer remains one of the major contributors to human mortality and a hazard to human growth. The search for a new treatment continues unabated. Aurora kinases play an important role in cell cycle, and thus a potential target for the treatment of cancer. In the present work, we aim to discover potential leads against aurora kinase using various rational methods of drug discovery. The available crystal complexes of AKs were analyzed for their interactions and quantified with glide-extra precision (XP) docking. About 20 crystal pdb were selected from the protein databank based on the resolution factor, R-factor and R-value. And after docking with the native ligands, the RMSD value was calculated, wherein the protein with the least RMSD was found to be 3UOK which was further used for our screening of small molecules from the in-house database by molecular docking. Fragments which were found to possess the best interactions were considered for the synthesis with characterization, and biological activity was carried out against breast cancer and colorectal cancer cell lines to assess the inhibitory capability of synthesized compounds. Molecule with the molecular id IS2 i.e. (3E)-3-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2H chromene-2,4(3H)-dione was found to possess inhibitory activity with an IC50 of 1.324nM and 5.785µM for breast cell line and colorectal cell line studies, respectively.

A tremendous research on Poly (ADP-ribose) polymerase (PARP) pertaining to cancer and ischemia is in very rapid progress. PARP’s are a specific class of enzymes that repairs the damaged DNA. Recent findings suggest also that PARP-1 is the most abundantly expressed nuclear enzyme which involves in various therapeutic areas like inflammation, stroke, cardiac ischemia, cancer and diabetes. The current review describes the overview on clinical candidates of PARP1 and its current status in clinical trials. This paper also covers identification of potent PARP1 inhibitors using structure and ligand based pharmacophore models. Finally 36 potential hits were identified from the virtual screening of pharmacophore models and screened for PARP1 activity. 15 actives were identified as potent PARP1 inhibitors and further optimization of these analogues are in progress.

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF’s) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.