NIPER, Kolkata; Department of Pharmacoinformatics
A pharmacy professional, Kuldeep Roy is the Assistant Professor at National Institute of Pharmaceutical Research (NIPER), Kolkata. His research spans hunt of disease therapeutics. He has a B. Pharm. degree in pharmacy discipline. His M.Pharm. degree specialized in pharmaceutical chemistry. He received Ph.D. in Medicinal Chemistry under the joint CSIR-Central Drug Research Institute (CSIR-CDRI)-Jawaharlal Nehru University (JNU) PhD program from CSIR-CDRI, Lucknow. His research involves both chemistry as well as drug design aimed towards the discovery of novel potential therapeutics. As recognition of his research, he has several peer-reviewed publications in international journals and three international patents.
NIPER, Kolkata; Department of Pharmacoinformatics
University of Mississippi, USA; Departments of Biomolecular Science
Ewha W. University, Seoul, South Korea; Department of Pharmaceutical and Life Sciences
CSIR-CDRI, Lucknow (INDIA); Division of Medicinal Chemistry
Ph.D. in Medicinal Chemistry
CSIR-CDRI, Lucknow, UP (INDIA)
Master of Pharmacy (Pharmaceutical Chemistry)
BIT, Mesra, Ranchi, JH (INDIA)
Bachelor of Pharmacy
BIT, Mesra, Ranchi, JH (INDIA)
The research group is aimed to design and develop new drug candidates for infectious diseases such as dengue, malaria and tuberculosis, as well as for selected neurodegenerative diseases like Alzheimer's disease. To achieve our goal, we are exploiting various cutting-edge structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches for the identification of novel small-molecule modulators of the targetted proteins, by the combination of computational and experimental approaches.
Being the Drug Repurposing as a Niche area of NIPER-K, we are extensively applying computational methods for discovering new uses for existing drugs for further development. Computational drug repurposing is appealing in putatively nominating the most promising candidate drugs for a given indication, and is attractive and pragmatic in view of the substantially lower cost and time requirements for drug development.
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). Despite immense efforts to develop new therapeutic agents, TB continues to be a top infectious disease worldwide. TB control is threatened by the continued spread of drug resistance. In 2014, 9.6 million people fell ill with TB and 1.5 million died from the disease. Moreover, an estimated 1 million children became ill with TB, and 140,000 children died of TB. In the same year, an estimated 480,000 people developed multidrug-resistant TB (MDR-TB), and various cases of extensively-drug resistant TB (XDR-TB) and totally-drug resistant TB (TDR-TB) have been established. Furthermore, TB is a leading killer of HIV-positive people: in 2015, 1 in 3 HIV deaths was due to TB. To combat the TB epidemic, the rapid development of better drugs capable of killing MDR-, XDR- and TDR-forms of Mycobacterium tuberculosis are urgently needed. The development of successful anti-tubercular agents simultaneously faces a myriad of challenges such as: meeting the directives of shortening treatment duration; dosing frequency; co-administration with HIV medications; and reducing adverse effects. Therefore, to bypass an era where various drug resistant TBs are continuously emerging, the discovery of novel inhibitory compounds targeting unique drug targets can be considered invaluable in terms of meeting the current and future therapeutic needs to relieve the huge global burden of resistant TB cases.
Dengue is a mosquito-borne viral infection causing flu-like illness, and occasionally develops into a potentially lethal complication called severe dengue. The global incidence of dengue has grown dramatically in recent decades, and warrants for a drug for its treatment. Since the drug repurposing (i.e. identifying and developing new uses for existing drugs) is attractive and pragmatic in view of the substantially lower cost and time requirements for drug development, we aim to identify and validate the new chemical entities targeting the inhibition of non-structural proteins implicated in the dengue replication.
Malaria is an infectious disease causing huge mortality and morbidity worldwide. Although antimalarial drugs are effective in several parts of the world, there is a serious threat to malaria control that malaria parasites are continuously developing widespread resistance against currently available antimalarial drugs, including artemisinin. Such widespread antimalarial drug resistance certifies the need of improving the efficacy of existing or new drugs, and developing alternative treatments through the identification of novel drug targets and development of candidate drugs.
Alzheimer's disease, a chronic neurodegenerative disease and the most common type of dementia, is an irreversible brain disorder in elderly patients in which the disease progressively gets worse. It slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. According to the World Alzheimer Report 2010, Alzheimer's Disease International estimated worldwide that there were 35.6 million people living with Alzheimer's disease in 2010, with a possible increase to 65.7 million by 2030 and 115.4 million by 2050. Alzheimer's disease is fatal, and currently, there is no cure. Currently, several molecules are in clinical pipeline, for example, 70 % are disease-modifying therapies (DMTs), 14 % are symptomatic cognitive enhancers, 13% are symptomatic agents and 2% have undisclosed mechanisms. But until date, none of these drugs has brought a fundamental breakthrough. There is a need of further research to attain the breakthrough in the near future for the treatment of AD, a disease of unmet need.
Computational Biology of Cell Signaling Proteins of Therapeutic Relevance
Cells classically receive signals via various signaling molecules, most of them are chemical in nature, such as growth factors, hormones, neurotransmitters, extracellular matrix components, etc.These signaling molecules exert effects locally, or they might travel over long distances. When a signaling molecule binds with an appropriate protein (receptor/enzyme) on a cell surface, such binding triggers a cascade of intracellular or extracellular events that not only conveys the signal to the cell interior, but to other cells. The GPCRs are key cellular signaling proteins and exceptionally prominent drug targets in the human genome, accountable for approximately 30-40% of all marketable drugs. These proteins regulate a large variety of physiological processes by sensing various signals and transmitting these signals to downstream effectors. Common physiological processes attributed to GPCRs include: modulation of neuronal signaling, regulation of ion transport within intracellular organelles and across the plasma membrane, regulation of cell division/proliferation, modification of cell morphology, and modulation of homeostasis. GPCRs are the most intensively investigated drug targets in the pharmaceutical industry. On the basis of sequence conservation, GPCRs have been grouped into five classes, with Class-A (Rhodopsin-like) being the largest and most studied. Focused on cell signaling proteins, we are exploring the following:
Exploration of structure, conformational landscapes, energetics, and dynamics of therapeutically-relevant cell signaling proteins.
Owing to remarkable advancements made in the X-ray crystallography and structural biology fields, there is a continuously increasing availability of many new and high-resolution X-ray crystal structures of several GPCRs with bound endogenous or synthetic ligand (categorized as agonist or inverse agonist or antagonist). The complete human genome sequencing has deciphered researchers, on one hand, the opportunity to study hundreds of novel GPCRs lacking any experimental structures, while on the other hand, represents an opportunity to advance our knowledge on the protein structure-function relationship as well as drug development by discovering ligands modulating these GPCRs.The challenge is to construct computational models that account for the effects of ligands on the energetic landscape of GPCR conformational states to forecast how these molecules will translate into definite pharmacological outcomes. Over the past few decades, there have been remarkable advancements made in the computational chemistry tools, including protein structure prediction tools, and there are many successes in the reliable prediction of unresolved GPCRs and other proteins feasible.
Affinity and Specificity among Cell Signaling Proteins (GPCRs or Kinases): Computational protocols to detect and validate allosteric binding sites for design of biased ligands.
Most of the important challenge in the targeted drug discovery is the identification of ligands as specific modulators of the particular GPCR or kinase of therapeutic relevance. So far, one of the most widely exploited approach for the search of targeted therapeutics is based on orthosteric site, as a site for endogenous ligand; orthosteric sites are understood to be more conserved among GPCRs, kinases and GPCR/Kinase-subtypes, and thus represent a challenge for the discovery of a safe drug. Compared to orthosteric site, allosteric sites, being topographically distinct from the orthosteric site, are less conserved among GPCRs or kinases, and thus, allosteric ligands can "fine-tune" classical pharmacological responses to effectively cure the specific disease. A significant growth in the identification of allosteric modulators of GPCRs and kinases has been witnessed in the past few decades. However, it still represents a grand challenge for detecting and validating allosteric sites in GPCRs and kinases. It will be considered as a significant advancement by unraveling the structural basis of allosteric modulation of GPCRs and kinases. Successful identification of allosteric sites can be used further to design and discover biased ligands targeting GPCRs or kinases.
Computational drug design and discovery of targeted therapeutics.
With remarkable advancements made in the area of structure biology and computational drug design tools, structure-based drug design (SBDD) has become an integral part of modern drug discovery phases, including for both lead generation and lead optimization. SBDD deciphers a proper understanding of the structural basis underlying interactions between receptors and their ligands, which is key for governing receptor affinity and specificity. There have been many success stories over the past two decades of the utility of SBDD approaches for the discovery of new scaffolds as well as for design of analogs with optimized affinity and specificity.In order to modulate the therapeutically-relevant downstream signaling process, the design of ligands, either as orthosteric or allosteric modulators, will depend on the particular target of research interest. An orthosteric agonist binds to the orthosteric site of the protein target and induces conformational changes resulting in the activation of downstream signaling pathways. By contrast, an allosteric modulator (AM), either positive, negative or neutral, binds to a site distinct from the orthosteric site, and enhances, decreases or does not affect, respectively, the affinity and/or efficacy of the orthosteric ligands. AMs lack intrinsic efficacy and exert effects only in the presence of an orthosteric ligand. AMs are preferred therapeutic agents that offer multiple competitive advantages over orthosteric ligands, such as higher selectivity/specificity for targets and lower chances of side effects.
β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series.
Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 ?M) and selectivity index (SI) values in the range of 4.5-197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between -9.375 and -14.55 units, compared to -9.137 for lapachol and -12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI.
Malaria is an infectious disease causing vast mortality and morbidity worldwide. Although antimalarial drugs are effective in several parts of the world, there is a serious threat to malaria control as malaria parasites are continuously developing widespread resistance against currently available antimalarial drugs, including artemisinin. Such widespread antimalarial drug resistance confirms the need to improve the efficacy of existing or new drugs as well as to develop alternative treatments through the identification of novel drug targets and the development of candidate drugs. Similar to proteases in other parasitic diseases such as leishmaniasis, schistosomiasis, Chagas disease and African sleeping sickness, malarial proteases constitute the major virulence factors in malaria. Malarial proteases belong to several classes and many of them have been targeted for the design and discovery of antimalarial agents. This review summarises the approaches, progress and challenges in the design of small-molecule inhibitors as antimalarial drugs targeting the inhibition of various malarial proteases.
Since the discovery of the GABA(B) agonist and muscle relaxant baclofen, there have been substantial advancements in the development of compounds that activate the GABA(B) receptor as agonists or positive allosteric modulators. For the agonists, most of the existing structure-activity data apply to understanding the role of substituents on the backbone of GABA as well as replacing the carboxylic acid and amine groups. In the cases of the positive allosteric modulators, the allosteric binding site(s) and structure-activity relationships are less well-defined; however, multiple classes of molecules have been discovered. The recent report of the X-ray structure of the GABA(B) receptor with bound agonists and antagonists provides new insights for the development of compounds that bind the orthosteric site of this receptor. From a therapeutic perspective, these data have enabled efforts in drug discovery in areas of addiction-related behavior, the treatment of anxiety, and the control of muscle contractility.
One of the most significant breakthroughs in the battle against tuberculosis is the recent approval of the quinoline compound, TMC207, for the treatment of drug-resistant tuberculosis. To gain insight into the molecular determinants of the activity of TMC207 and to evaluate the scope of quinoline compounds as anti-tubercular agents, we synthesized a series of TMC207 derivatives and evaluated their anti-tubercular activity. Making the lateral chain of the drug rigid by linking it to an adjacent phenyl substituent resulted in a decrease in activity. In contrast, replacing a phenyl substituent of TMC207 with a quinoline moiety gave bisquinolines that demonstrated potent anti-tubercular activity in in vitro experiments, in ex vivo mouse bone marrow macrophage assays, and also in the in vivo mouse model of the disease. These results provide new guiding principles for modifying the TMC207 scaffold to develop efficacious anti-tubercular drugs and set the stage for the development of bisquinolines as a promising new class of anti-tubercular agents.
The mycobacterial F0F1-ATP synthase (ATPase) is a validated target for the development of tuberculosis (TB) therapeutics. Therefore, a series of eighteen novel compounds has been designed, synthesized and evaluated against Mycobacterium smegmatis ATPase. The observed ATPase inhibitory activities (IC50) of these compounds range between 0.36 and 5.45?M. The lead compound 9d [N-(7-chloro-2-methylquinolin-4-yl)-N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-2,3-dichlorobenzenesulfonamide] with null cytotoxicity (CC50>300?g/mL) and excellent anti-mycobacterial activity and selectivity (mycobacterium ATPase IC50=0.51?M, mammalian ATPase IC50>100?M, and selectivity >200) exhibited a complete growth inhibition of replicating Mycobacterium tuberculosis H37Rv at 3.12?g/mL. In addition, it also exhibited bactericidal effect (approximately 2.4log10 reductions in CFU) in the hypoxic culture of non-replicating M. tuberculosis at 100?g/mL (32-fold of its MIC) as compared to positive control isoniazid [approximately 0.2log10 reduction in CFU at 5?g/mL (50-fold of its MIC)]. The pharmacokinetics of 9d after p.o. and IV administration in male Sprague-Dawley rats indicated its quick absorption, distribution and slow elimination. It exhibited a high volume of distribution (Vss, 0.41L/kg), moderate clearance (0.06L/h/kg), long half-life (4.2h) and low absolute bioavailability (1.72%). In the murine model system of chronic TB, 9d showed 2.12log10 reductions in CFU in both lung and spleen at 173?mol/kg dose as compared to the growth of untreated control group of Balb/C male mice infected with replicating M. tuberculosis H37Rv. The in vivo efficacy of 9d is at least double of the control drug ethambutol. These results suggest 9d as a promising candidate molecule for further preclinical evaluation against resistant TB strains.
Truncated N(6)-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N(6) and/or C2 substituents were tolerated in A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N(6)-cycloalkyl group (4d) showed excellent binding affinity at the hA3AR and was better than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with Ki values of 7.8-16.0 nM. N(6)-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects in human TGF-?1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-?1-induced collagen I upregulation, and their A3AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 ?M), indicating its potential as a good therapeutic candidate for treating renal fibrosis.
The mycobacterial Rv3097c-encoded lipase LipY is considered as a true lipase involved in the hydrolysis of triacylglycerol stored in lipid inclusion bodies for the survival of dormant mycobacteria. To date, orlistat is the only known LipY inhibitor. In view of the important emerging role of this enzyme, a search for small-molecule inhibitors of LipY was made, leading to the identification of some new compounds (8a-8d, 8f, 8h and 8i) with potent inhibitory activities against recombinant LipY, with no cytotoxicity [50% inhibitory concentration (CC(50)) ? 500 ?g/mL]. The compounds 6a, 8c and 8f potently inhibited (>90%) the growth of Mycobacterium tuberculosis H37Rv grown under hypoxia (oxygen-depleted condition) but had no effect on aerobically grown bacilli, suggesting that these new small molecules are highly selective towards the growth inhibition of hypoxic cultures of M. tuberculosis and hence provide new leads for combating latent tuberculosis.
The present invention relates to novel substituted 1,2,3,4-tetrahydroquinolin-7-yl carbamates, their preparation, and use as therapeutic agents, particularly in the prevention or treatment of neurodegenerative or Alzheimer's disease, or senile dementia, or memory disturbances, and more particularly to the prevention, treatment and amelioration of Alzheimer's disease with the novel substituted 1,2,3,4-tetrahydroquinolin-7-yl carbamates, which act as inhibitors of central cholinesterase enzymes, particularly acetylcholinesterase (AChE) following the indirect cholinomimetic pathway. The present invention particularly relates to compounds of formula A: Formula A wherein R1=alkyl, aryl, substituted aryl; R2=H, methyl; R3=H, alkyl, alkenyl, alkynyl, aralkyl, substituted aralkyl, aryl, heteroaryl.
The present invention relates to novel N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-N-(quinolin-4- yl)sulfonamide derivatives, their preparation, to pharmaceutical compositions comprising them, and to their use as therapeutic agents, particularly in the prevention or treatment of tuberculosis. The present invention particularly relates to compounds of formula A[Formula I]: wherein: R = methyl, (or) R = a group of the structure [Formula II] wherein, R1, R2, and R3 may be same or different present at any position(s) and are groups selected from the group consisting of hydrogen, halogen, alkyl (C1-C3), nitro, cyano, trifluoromethyl, (or) R is a group of the structure [Formula III] wherein X may be CH or N, and the attachment point of sulfonyl may be at the position 1 or 2, (or) R is a group of the structure [Formula IV] Where R1 is hydrogen or halogen, (or) R is a group of the structure.
The ATP synthase of Mycobacterium tuberculosis is a validated drug target against which a diarylquinoline drug is under clinical trials. The enzyme is crucial for the viability both of actively replicating and non-replicating/dormant M. tuberculosis. Enzyme levels drop drastically as the bacilli enter dormancy and hence an inhibitor would make the dormant bacilli even more vulnerable. In this study, a set of 18 novel substituted chloroquinolines were screened against Mycobacterium smegmatis ATP synthase; 6 compounds with the lowest 50% inhibitory concentration (IC(50)) values (0.36-1.83 ?M) were selected for further in vitro studies. All six compounds inhibited the growth of M. tuberculosis H37Rv in vitro, with minimum inhibitory concentrations (MICs) of 3.12 ?g/mL (two compounds) or 6.25 ?g/mL (four compounds). All of them were bactericidal to non-replicating M. tuberculosis H37Rv in hypoxic culture; three compounds caused a >2 log(10) reduction in CFU counts in 4 days at concentrations of 16� or 32� their MICs, compared with a 0.2 log(10) reduction by isoniazid and a >4 log(10) reduction by rifampicin at 100� their MICs. The compounds also contributed to a greater reduction in total cellular ATP of the bacilli compared with isoniazid and rifampicin during an exposure time of 18 h. The compounds at 100 ?M caused only 5-35% inhibition of mouse liver mitochondrial ATP synthase, leading to selectivity indices ranging from >55-fold to >278-fold. In vitro cytotoxicity to the Vero cell line measured as the 50% cytotoxic concentration (CC(50)) of the compounds ranged between 55 ?g/mL and >300 ?g/mL.
The hierarchical virtual screening (HVS) study, consisting of pharmacophore modelling, docking and VS of the generated focussed virtual library, has been carried out to identify novel high-affinity and selective β3-adrenergic receptor (β3-AR) agonists. The best pharmacophore model, comprising one H-bond donor, two hydrophobes, one positive ionizable and one negative ionizable feature, was developed based on a training set of 51 β3-AR agonists using the pharmacophore generation protocol implemented in Discovery Studio. The model was further validated with the test set, external set and ability of the pharmacophoric features to complement the active site amino acids of the homology modelled β3-AR developed using MODELLER software. The focussed virtual library was generated using the structure-based insights gained from our earlier reported comprehensive study focussing on the structural basis of β-AR subtype selectivity of representative agonists and antagonists. The HVS with the sequential use of the best pharmacophore model and homology modelled β3-AR in the screening of the generated focussed library has led to the identification of potential virtual leads as novel high-affinity and selective β3-AR agonists.
The present invention relates to novel substituted 4-arylthiazoles, their preparation, and to their use as therapeutic agents, particularly in the prevention or treatment of tuberculosis. The resent invention articularl relates to com ounds of formula A.
The optimization of our previous lead compound 1 (AChE IC(50)=3.31 ?M) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC(50)=2.57?M), 6b (IC(50)=0.70 ?M) and 6i (IC(50)=2.56 ?M) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC(50)=1.11 ?M). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE-carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE-carbamate Michaelis complexes have been investigated.
Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme's binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitors.
In search of potential therapeutics for tuberculosis, we describe herein synthesis and biological evaluation of some substituted 4-arylthiazol-2-amino derivatives as modified analogues of the antiprotozoal drug Nitazoxanide (NTZ), which has recently been reported as potent inhibitor of Mtb H(37)Rv (Mtb MIC=52.12 ?M) with an excellent ability to evade resistance. Among the synthesized derivatives, the two compounds 7a (MIC=15.28 ?M) and 7c (MIC=17.03 ?M) have exhibited about three times better Mtb growth inhibitory activity over NTZ and are free from any cytotoxicity (Vero CC(50) of 244 and 300 ?M respectively). These two compounds represent promising leads for further optimization.
The current study deciphers the combined ligand- and structure-based computational insights to profile structural determinants for the selectivity of representative diverse classes of FXa-selective and thrombin-selective as well as dual FXa-thrombin high affinity inhibitors. The thrombin-exclusive insertion 60-loop (D-pocket) was observed to be one of the most notable recognition sites for the known thrombin-selective inhibitors. Based on the topological comparison of four common active-site pockets (S1-S4) of FXa and thrombin, the greater structural disparity was observed in the S4-pocket, which was more symmetrical (U-shaped) in FXa as compared to thrombin mainly due to the presence of L99 and I174 residues in latter in place of Y99 and F174 respectively in former protease. The S2 pocket forming partial roof at the entry of 12 � deep S1-pocket, with two extended ?-sheets running antiparallel to each other by undergoing U-turn (?180?), has two conserved glycine residues forming H-bonds with the bound ligand for governing ligand binding affinity. The docking, scoring, and binding pose comparison of the representative high-affinity and selective inhibitors into the active sites of FXa and thrombin revealed critical residues (S214, Y99, W60D) mediating selectivity through direct- and long-range electrostatic interactions. Interestingly, most of the thrombin-selective inhibitors attained S-shaped conformation in thrombin, while FXa-selective inhibitors attained L-shaped conformations in FXa. The role of residue at 99th position of FXa and thrombin toward governing protease selectivity was further substantiated using molecular dynamics simulations on the wild-type and mutated Y99L FXa bound to thrombin-selective inhibitor 2. Furthermore, predictive CoMFA (FXa q� = 0.814; thrombin q� = 0.667) and CoMSIA (FXa q� = 0.807; thrombin q� = 0.624) models were developed and validated (FXa r�(test) = 0.823; thrombin r(2)(test) = 0.816) to feature molecular determinants of ligand binding affinity using the docking-based conformational alignments (DBCA) of 141 (88(train)+53(test)) and 39 (27(train)+11(test)) nonamidine class of potent FXa (0.004 ? K(i) (nM) ? 4700) and thrombin (0.001 ? K(i) (nM) ? 940) inhibitors, respectively. Interestingly, the ligand-based insights well corroborated with the structure-based insights in terms of the role of steric, electrostatic, and hydrophobic parameters for governing the selectivity for the two proteases. The new computational insights presented in this study are expected to be valuable for understanding and designing potent and selective antithrombotic agents.
The integrated ligand- and structure-based drug design techniques have been applied on a homogeneous dataset of thiolactone-class of potent anti-malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum. Developed CoMFA (q(2) = 0.716) and CoMSIA (q(2) = 0.632) models well explained structure-activity variation in both the training (CoMFA R(2) = 0.948 & CoMSIA R(2) = 0.849) and test set (CoMFA R(2) (pred) = 0.789 & CoMSIA R(2) (pred) = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high-resolution (2.35 �) structure of FabB-TLM binary complex (PDB-ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H-bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein-ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone-class of compounds that could furnish improved anti-malarial activity.
The β3-adrenegic receptor (β3-AR) selectivity over β1 and β2-ARs has been the most important aspect for successful therapeutic agents for obesity and type-II diabetes, as the concomitant activation of β1 and &beta'2-ARs would lead to undesirable side effects, such as increased heart rate. In order to explore the structural basis for the β-AR subtype selectivity of agonists and anatagonists, a three-dimensional structure of until date unresolved β3-AR has been modeled, compared with the resolved X-ray structures of β1 and β2-ARs, and used to study its stereoselective binding with until-date known diverse classes of representative agonists and antagonist. The obtained binding structures and calculated prime molecular mechanics-generalized Born surface area (MM-GBSA) binding free energies consistently reveal that while the subtype selectivity is strongly governed by the residues present in the extracellular ends of TM3, TM5, TM6, TM7 helices and of the ECL2 domain, the binding affinity is governed by the conserved residues present in the deep pocket limiting the degree of conformational and rotational freedoms to the bound ligand. The study demonstrates that the key structural requirements for the ?(3)-selectivity are: (i) a negatively ionizable group (NIG) for direct interaction with β3-specific residue R315(6.58), (ii) a linker (9-10 � length) between the protonated amine and NIG, and (iii) a substituted aryl ring directly attached to the β-hydroxyl carbon. The new computational insights acquired in this study are expected to be valuable in structure-based rational design of high-affinity agonists and antagonists with pronounced β3-selectivity for successful therapeutic agents for type-II diabetes and obesity.
The present study describes a systematic 3D-QSAR study consisting of pharmacophore modeling, docking, and integration of ligand-based and structure-based drug design approaches, applied on a dataset of 72 Hsp90 inhibitors as anti-cancer agents. The best pharmacophore model, with one H-bond donor (HBD), one H-bond acceptor (HBA), one hydrophobic_aromatic (Hy_Ar), and two hydrophobic_aliphatic (Hy_Al) features, was developed using the Catalyst/HypoGen algorithm on a training set of 35 compounds. The model was further validated using test set, external set, Fisher's randomization method, and ability of the pharmacophoric features to complement the active site amino acids. Docking analysis was performed using Hsp90 chaperone (PDB-Id: 1uyf) along with water molecules reported to be crucial for binding and catalysis (Sgobba et al. ChemMedChem 4:1399-1409, 2009). Furthermore, an integration of the ligand-based as well as structure-based drug design approaches was done leading to the integrated model, which was found to be superior over the best pharmacophore model in terms of its predictive ability on internal [integrated model 2: R ((train)) = 0.954, R ((test)) = 0.888; Hypo-01: R ((train)) = 0.912 and R ((test)) = 0.819] as well as on external data set [integrated model 2: R ((ext.set)) = 0.801; Hypo-01: R ((ext.set)) = 0.604].
A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.
In view of the nonavailability of complete X-ray structure of carbamates cocrystallized with AChE enzyme, the 3D-QSAR model development based on cocrystallized conformer (CCBA) as well as docked conformer-based alignment (DCBA) is not feasible. Therefore, the only two alternatives viz. pharmacophore and maximum common substructure-based alignments are left for the 3D-QSAR comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analyses (CoMSIA) model development. So, in the present study, the 3D-QSAR models have been developed using both alignment methods, where CoMFA and CoMSIA models based on pharmacophore-based alignment were in good agreement with each other and demonstrated significant superiority over MCS-based alignment in terms of leave-one-out (LOO) cross-validated q(2) values of 0.573 and 0.723 and the r(2) values of 0.972 and 0.950, respectively. The validation of the best CoMFA and CoMSIA models based on pharmacophore (Hip-Hop)-based alignment on a test set of 17 compounds provided significant predictive r(2) [r(2)(pred(test))] of 0.614 and 0.788, respectively. The contour map analyses revealed the relative importance of steric, electrostatic, and hydrophobicity for AChE inhibition activity. However, hydrophobic factor plays a major contribution to the AChE inhibitory activity modulation which is in strong agreement with the fact that the AChE is having a wide active site gorge (approximately 20 A) occupied by a large number of hydrophobic amino acid residues.
In search of potent β3-adrenergic receptor agonists, a series of novel substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes has been synthesized and evaluated for their β3-adrenergic receptor agonistic activity (ranging from -17.73% to 90.64% inhibition at 10 microM) using well established Human SK-N-MC neuroblastoma cells model. Four molecules viz. 11, 15, 22 and 23 showed β3-AR agonistic IC(50) value of 0.55, 0.59, 1.18 and 1.76 microM, respectively. These four candidates have been identified as possible leads for further development of beta(3)-adrenergic receptor agonists for obesity and Type-II diabetes pharmacotherapy. The free OH and NH functions are found to be essential for β3-adrenergic receptor agonistic activity. Among the synthesized β3-adrenergic receptor agonists having 1,2,3,4-tetrahydroquinoline scaffold, the N-benzyl group is found to be superior over N-arylsulfonyl group. A putative pharmacophore model has been modeled considering the above four active molecules which distinguishes well between the active and inactive molecules.
In order to identify the essential structural features and physicochemical properties for acetylcholinesterase (AChE) inhibitory activity in some carbamate derivatives, the systematic QSAR (Quantitative Structure Activity Relationship) studies (CoMFA, advance CoMFA and CoMSIA) have been carried out on a series of (total 78 molecules) taking 52 and 26 molecules in training and test set, respectively. Statistically significant 3D-QSAR (three-dimensional Quantitative Structure Activity Relationship) models were developed on training set molecules using CoMFA and CoMSIA and validated against test set compounds. The highly predictive models (CoMFA q(2)=0.733, r(2)=0.967, predictive r(2)=0.732, CoMSIA q(2)=0.641, r(2)=0.936, predictive r(2)=0.812) well explained the variance in binding affinities both for the training and the test set compounds. The generated models suggest that steric, electrostatic and hydrophobic interactions play an important role in describing the variation in binding affinity. In particular the carbamoyl nitrogen should be more electropositive; substitutions on this nitrogen should have high steric bulk and hydrophobicity while the amino nitrogen should be electronegative in order to have better activity. These studies may provide important insights into structural variations leading to the development of novel AChE inhibitors which may be useful in the development of novel molecules for the treatment of Alzheimer's disease.
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