Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.

Testing of groundwater used for drinking for arsenic has been undertaken more widely by state governments in several states of India in recent years with the support of UNICEF. Available data for five states are collated in this paper and this provides the most up-to-date picture of areas known to be affected by arsenic in groundwater in the Indian portion of the Ganges-Brahmaputra river basin. In West Bengal, water from 132,262 government installed handpumps in 8 districts has been tested and overall 25.5% of samples were found to contain arsenic at concentrations greater than 50 μ gL⁻¹ and 57.9% at concentrations greater than 10 μ gL⁻¹. On the banks of the Brahmaputra in Assam, to date, samples from 5,729 government handpump sources in 22 districts have been tested for arsenic. Overall, samples from 6.3% of sources were found to contain arsenic at concentrations greater than 50 μ gL⁻¹ and 26.1% at concentrations greater than 10 μ gL⁻¹. In Bihar, on the River Ganges upstream of West Bengal, 66,623 sources from 11 districts have been tested and water samples from 10.8% of sources were found to contain arsenic at concentrations greater than 50 μ gL⁻¹ and 28.9% at concentrations greater than 10 μ gL⁻¹. Upstream of Bihar in Uttar Pradesh, home of the Taj Mahal, to date water samples from 20,126 government-installed handpump sources have been tested. As a result 2.4% of the samples tested were found to contain arsenic at concentrations greater than 50 μ gL⁻¹ and 21.5% at concentrations greater than 10 μ gL⁻¹. Finally in one district of Jharkhand, lying on the Ganges alluvial plain between Bihar and West Bengal, 9,007 sources have been tested and water samples from 3.7% of sources were found to contain arsenic at concentrations greater than 50 μ gL⁻¹ and 7.5% at concentrations greater than 10 μ gL⁻¹. State governments have adopted different sampling strategies and these are described in this paper. Testing is ongoing in several states and the complete picture is yet to emerge in some areas.

The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved in the pathophysiology of Alzheimer’s disease by phosphorylating the serine residue in SR proteins. Nuclear speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer’s disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40 nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also highlighted.

α-Glucosidase (EC 3.2.1.20) enzyme belongs to the glycosidase family enzymes, cleave the glycosidic bond of the oligosaccharides that liberate glucose and its inhibition retards the carbohydrate digestion. In the present review, we have discussed the structural features of different α-glucosidase inhibitors (small molecules) responsible for the inhibitory activities. The reported computational studies including, QSAR, pharmacophore modelling, homology models, docking (with analogs enzymes), etc revealed that the topological, electronic and hydrophobicity properties determine the interactions of those molecules. The aromatic substituents connected with flexible bonds in the molecules have significant effect on the interactions, which may due to the presence of aromatic amino acid residues in the active site. The reported homology modelled and other analogs enzymes (enzymes of other species) also confirmed the existence of aromatic residue (amino acids) especially, histidine, phenylalanine and tyrosine in their active site along with the polar (glutamic and aspartic acids) residues. Multiple sequence alignments of the α-glucosidase enzymes (from different species) described that the abovementioned amino acid residues are present in the active site of all the studied enzymes. Recently, Celgosivir (MIGENIX Inc) is an oral prodrug of the natural product castanospermine used for the treatment of HCV infection by inhibiting α-glucosidase I. BMN-701 is an α-glucosidase inhibitors in the phase I pipeline (BioMarine) for the treatment of Pompe diseases. CKD-711 and CKD-711a are aminooligosaccharide α-glucosidase inhibitors and the in vitro study of CKD-711 showed similar effects to acarbose on porcine intestinal maltase and sucrase (IC50s of 2.5 and 0.5 μg/ml). This review also concluded that many α-glucosidases inhibitors obtained from natural products are used for the treatment of various carbohydrate mediated diseases. The structural analysis of these synthetic and natural derivatives guide for the development of novel semisynthetic/synthetic α-glucosidase inhibitors with free of toxicities.

6H-Indolo[2,3-b]quinoxaline, a planar fused heterocyclic compound exhibits a wide variety of pharmacological activities. The mechanism of pharmacological action exerted by these compounds is predominantly DNA intercalation. The thermal stability of the intercalated complex (DNA and 6H-indolo[2,3-b]quinoxaline derivatives) is an important parameter for the elucidation of anticancer, antiviral and other activities. This thermal stability of the 6H-indolo[2,3- b]quinoxaline–DNA complex depends on the type of substituents and side chains attached to the 6H-indolo[2,3- b]quinoxaline nucleus and also the orientation of the side chain towards the GC rich minor groove of the DNA. Highly active 6H-indolo[2,3-b]quinoxaline derivatives such as NCA0424, B-220 and 9-OH-B-220 have shown good binding affinity to DNA as evident from high thermal stability of compound-DNA complex. Interestingly, these compounds possessed poor inhibitory activity on topoisomerase II enzyme but have significant MDR modulating activity. This review establishes ‘6H-indolo[2,3-b]quinoxaline’ as a valuable template for design and development of novel molecules with different biological activities.

Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn²⁺ ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacokinetic properties in the clinical studies.