Manjunath Ghate

Homology modeling a fast tool for drug discovery: Current perspectives

Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery.

Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors.

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention. Inhibitors of DHODH have proven efficacy for the treatment of malaria, autoimmune diseases, cancer, rheumatoid arthritis and psoriasis. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) represents an important target for the treatment of malaria. Many of the clinically relevant anti-tumor and immunosuppressive drugs target human dihydroorotate dehydrogenase (hDHODH), and the two most promising drugs of such kinds are brequinar (antitumor and immunosuppressive) and leflunomide (immunosuppressive). X-ray crystal structures of DHODH in complex with inhibitors reveal common binding region shared by each inhibitor. A number of compounds are identified by high-throughput screening (HTS) of chemical libraries and structure-based computational approaches as selective DHODH inhibitors. Based upon the understanding of molecular interaction of DHODH inhibitors with binding site, some of the common structural features are identified like ability of compounds to interact with ubiquinone (CoQ) binding site and substituents linked to a variety of heterocyclic and heteroaromatic rings responsible for H-bonding with binding site. These findings provide new approaches to design DHODH inhibitors and highlights DHODH as a target for chemotherapeutics. This review is mainly focused on the recent developments in the medicinal chemistry and therapeutic potential of DHODH inhibitors as a target for drug discovery.

Pharmacophore modeling, virtual screening, docking and in silico ADMET analysis of protein kinase B (PKB β) inhibitors

Protein kinase B (PKB) is a key mediator of proliferation and survival pathways that are critical for cancer growth. Therefore, inhibitors of PKB are useful agents for the treatment of cancer. Herein, we describe pharmacophore-based virtual screening combined with docking study as a rational strategy for identification of novel hits or leads. Pharmacophore models of PKB β inhibitors were established using the DISCOtech and refined with GASP from compounds with IC50 values ranging from 2.2 to 246nM. The best pharmacophore model consists of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) site and two hydrophobic (HY) features. The pharmacophore models were validated through receiver operating characteristic (ROC) and Güner-Henry (GH) scoring methods indicated that the model-3 was statistically valuable and reliable in identifying PKB β inhibitors. Pharmacophore model as a 3D search query was searched against NCI database. Several compounds with different structures (scaffolds) were retrieved as hits. Molecules with a Qfit value of more than 95 and three other known inhibitors were docked in the active site of PKB to further explore the binding mode of these compounds. Finally in silico pharmacokinetic and toxicities were predicted for active hit molecules. The hits reported here showed good potential to be PKB β inhibitors.

Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4 (DPP-4) inhibitors.

Dipeptidyl peptidase-4 (DPP-4) is one of the widely explored novel targets for Type 2 diabetes mellitus (T2DM) currently. Research has been focused on the strategy to preserve the endogenous glucagon like peptide (GLP)-1 activity by inhibiting the DPP-4 action. The DPP-4 inhibitors are weight neutral, well tolerated and give better glycaemic control over a longer duration of time compared to existing conventional therapies. The journey of DPP-4 inhibitors in the market started from the launch of sitagliptin in 2006 to latest drug teneligliptin in 2012. This review is mainly focusing on the recent medicinal aspects and advancements in the designing of DPP-4 inhibitors with the therapeutic potential of DPP-4 as a target to convey more clarity in the diffused data.

Novel Research Strategies of Benzimidazole Derivatives: A Review

Benzimidazole plays an important role in the medicinal chemistry and drug discovery with many pharmacological activities which have made an indispensable anchor for discovery of novel therapeutic agents. Substitution of benzimidazole nucleus is an important synthetic strategy in the drug discovery process. Therapeutic properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize novel therapeutic agents. Therefore, it is required to couple the latest information with the earliest information to understand the current status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for the development of SAR on benzimidazoles for each activity. This article aims to review the work reported, chemistry and pharmacological activities of benzimidazole derivatives during past years.

Recent advances and therapeutic journey of coumarins: current status and perspectives

Coumarins are oxygen-containing molecules with specific benzopyrone nucleus. Different coumarins are identified as antineurodegeneratives, anticoagulants, antioxidants, antimicrobials, anticancers, antivirals, antidiabetics, antidepressants, supramoleculars, antiparasitics, anti-inflammatory, analgesics, biological stains, pathological probes and diagnostics. Coumarins have received more attention as compared to 1-azacoumarins. Many attempts have been made for the comparison of both the systems at different stages to discover novel synthetic methodologies, reactivity strategies and biological activities. Translation of current knowledge into novel potent lead compounds and repositioning of well-known compounds for the treatment of different acute and chronic diseases are the current challenges of coumarins. This review article focusses on the occurence, synthesis and specific biological activities of various coumarin derivatives. Some novel research approaches are also described for the discovery and development of new synthetic strategies that could help in structure–activity relationship (SAR) studies. Cellular and molecular mechanisms of coumarins involved in SAR studies are also described.

Synthesis, characterization and antimicrobial studies of 2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4] triazolo-3-ones and their corresponding sulfones

In the present investigation, a series of novel 2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4] triazolo-3-ones and their corresponding sulfones were prepared with the objective of developing better antimicrobial agents. The chemical structures of the newly synthesized compounds were characterized by spectral (IR, (1)H NMR, (13)C NMR and LCMS) methods. The newly synthesized compounds (4a-i) and (5a-e, 5h) were screened for their antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa. The antifungal activity was tested against Rhizopus oryzae, Aspergillus niger, Aspergillus flavus, Candida albicans and Saccharomyces cerevisiae. Among all the compounds synthesized, compounds 4d and 5b exhibited significant antibacterial activity.

Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review.

The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluid-electrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems. The RAS can be inhibited at various points to control pathogenesis of hypertension. Renin inhibitors and angiotensin-converting enzyme (ACE) inhibitors were the earliest RAS blocking agents. A relatively new class of compounds known as Ang II receptor antagonists (SARTANs) is developed for the treatment of hypertension. They exert their action by blocking the binding of Ang II on AT(1) receptor. Angiotensin converting enzyme (ACE) inhibitors are associated with incident of side effects such as cough and angioedema while clinical trials with Ang II receptor antagonists have confirmed that these drugs are safe and efficacious for the treatment of hypertension. Based upon the understanding of molecular interaction of Ang II receptor antagonists with AT(1) receptor some of the common structural features have been identified, such as a heterocyclic (nitrogen atom) ring system, an alkyl side chain and an acidic tetrazole group. Research efforts for development of new molecules with similar structural features have led to the discovery of various non-peptidic Ang II receptor antagonists with different substituted heterocyclic such as imidazole (losartan) and benzimidazole (candesartan and telmisartan). In this study we have critically reviewed various benzimidazole substituted compounds as Ang II-AT(1) receptor antagonists and explored other potential clinical uses for this class of compounds.

2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Background The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors, the quantitative structure–activity relationship (QSAR) approach became very useful and largely widespread technique forligand-based drug design. Methods We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-thiadiazole thioacetanilides analogues to elucidate the structural properties required for HIV-RT inhibitory activity. Results The 2D-QSAR studies were performed using multiple linear regression method, giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2 = 0.89 and a non-cross-validated correlation coefficient r2 = 0.97 were obtained. Docking analysis suggests that the new series have comparable binding affinity with the standard compounds. Conclusions This approach showed that hydrophobic and electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.

Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives

In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH3 group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity.