Yogesh A Sabnis

Central Drug Research Institute, Lakhnau, Uttar Pradesh, India

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Publications (16)44.23 Total impact

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    ABSTRACT: We have investigated the influence of post-filtering virtual screening results, with pharmacophoric features generated from an X-ray structure, on enrichment rates. This was performed using three docking softwares, zdock+, Surflex and FRED, as virtual screening tools and pharmacophores generated in UNITY from co-crystallized complexes. Sets of known actives along with 9997 pharmaceutically relevant decoy compounds were docked against six chemically diverse protein targets namely CDK2, COX2, ERalpha, fXa, MMP3, and NA. To try to overcome the inherent limitations of the well-known docking problem, we generated multiple poses for each compound. The compounds were first ranked according to their scores alone and enrichment rates were calculated using only the top scoring pose of each compound. Subsequently, all poses for each compound were passed through the different pharmacophores generated from co-crystallized complexes and the enrichment factors were re-calculated based on the top-scoring passing pose of each compound. Post-filtering with a pharmacophore generated from only one X-ray complex was shown to increase enrichment rates in all investigated targets compared to docking alone. This indicates that this is a general method, which works for diverse targets and different docking softwares.
    Journal of Molecular Graphics and Modelling 07/2008; 26(8):1237-51. · 2.33 Impact Factor
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    ABSTRACT: Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1-P3 cyclization, which gave products with inhibition constants in the nanomolar range ( approximately 75nM).
    Bioorganic & Medicinal Chemistry 03/2007; 15(3):1448-74. · 2.90 Impact Factor
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    ABSTRACT: There is an urgent need for more efficient therapies for people infected with hepatitis C virus (HCV). HCV NS3 protease inhibitors have shown proof-of-concept in clinical trials, which make the virally encoded NS3 protease an attractive drug target. Product-based NS3 protease inhibitors comprising a P1 C-terminal carboxylic acid have shown to be effective and we were interested in finding alternatives to this crucial carboxylic acid group. Thus, a series of diverse P1 functional groups with different acidity and with possibilities to form a similar, or an even more powerful, hydrogen bond network as compared to the carboxylic acid were synthesized and incorporated into potential inhibitors of the NS3 protease. Biochemical evaluation of the inhibitors was performed in both enzyme and cell-based assays. Several non-acidic C-terminal groups, such as amides and hydrazides, were evaluated but failed to produce inhibitors more potent than the corresponding carboxylic acid inhibitor. The tetrazole moiety, although of similar acidity to a carboxylic acid, provided an inhibitor with mediocre potencies in both assays. However, the acyl cyanamide and the acyl sulfinamide groups rendered compounds with low nanomolar inhibitory potencies and were more potent than the corresponding carboxylic acid inhibitor in the enzymatic assay. Additionally, results from a pH-study suggest that the P1 C-terminal of the inhibitors comprising a carboxylic acid, an acyl sulfonamide or an acyl cyanamide group binds in a similar mode in the active site of the NS3 protease.
    Bioorganic & Medicinal Chemistry 01/2007; 15(12):4057-4068. · 2.90 Impact Factor
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    ABSTRACT: In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.
    Bioorganic & Medicinal Chemistry 09/2006; 14(15):5303-15. · 2.90 Impact Factor
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    ABSTRACT: The hepatitis C virus (HCV) NS3 protease has emerged as a promising anti-HCV drug target. Herein, we present an investigation of NS3 inhibitors comprising the acyl sulfonamide functionality. A series of tetra- and tripeptide based acyl sulfonamide inhibitors and their structure-activity relationships from both enzymatic and cell-based in vitro assays are presented. In summary, the acidity of the acyl sulfonamide functionality, the character of the P1 side chain, and the acyl sulfonamide substituent were found to be important for the inhibitory potencies.
    Bioorganic & Medicinal Chemistry 02/2006; 14(2):544-59. · 2.90 Impact Factor
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    ABSTRACT: The increasing resistance of the malarial parasite to antimalarial drugs is a major contributor to the reemergence of the disease and increases the need for new drug targets. The two aspartic proteases, plasmepsins I and II, from Plasmodium falciparum have recently emerged as potential targets. In an effort to inhibit these hemoglobinases, a series of inhibitors encompassing a basic hydroxyethylamine transition state isostere as a central fragment were prepared. The synthesized compounds were varied in the P1' position and exhibited biological activities in the range of 31 to >2000 nM. To try to rationalize the results, molecular docking and 3D-QSAR analysis were used.
    Bioorganic & Medicinal Chemistry 10/2005; 13(18):5371-90. · 2.90 Impact Factor
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    ABSTRACT: The Plasmodium falciparum cysteine proteases, falcipains, have been established as novel targets for antimalarial drug design. Using the de novo design approach, several trisubstituted thiazole analogs were generated as potential inhibitors of these enzymes. A general and convenient synthetic approach for these novel trisubstituted thiazoles is reported here. Substituents at the 4th and 5th positions of the target thiazoles were introduced by a Hantzsch reaction, and the chain at the second position was extended through a Sandmeyer reaction, formylation, and Wittig olefination. In vitro enzyme inhibition studies have identified three inhibitors (14, 16, 23) of the falcipains with one (14) showing dual activity against both falcipain-2 and falcipain-3 and IC50 values of 6.6 and 29.4 μM, respectively.
    Medicinal Chemistry Research 01/2005; 14(2):74-105. · 1.61 Impact Factor
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    ABSTRACT: Trypanosomiasis, leishmaniasis, and malaria are major parasitic diseases in developing countries. The existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance. Cysteine proteases are exciting novel targets for antiparasitic drug design. Virtual screening was performed in an attempt to identify novel druglike nonpeptide inhibitors of parasitic cysteine proteases. The ChemBridge database consisting of approximately 241 000 compounds was screened against homology models of falcipain-2 and falcipain-3 in three consecutive stages of docking. A total of 24 diverse inhibitors were identified from an initial group of 84, of which 12 compounds appeared to be dual inhibitors of falcipain-2 and falcipain-3. Four compounds showed inhibition of both the malarial cysteine proteases as well as Leishmania donovani cysteine protease.
    Journal of Medicinal Chemistry 01/2005; 47(26):6609-15. · 5.61 Impact Factor
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    ABSTRACT: 1,4,7-Trisubstituted isoquinolines were designed, synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2. The 1-benzyloxyphenyl-dihydroisoquinoline and -isoquinoline derivatives were found to exhibit better activity against falcipain-2 than their corresponding 1-hydroxyphenyl or 1-methoxyphenyl analogues. The docking scores correlate with the IC(50) values of compounds and give a high coefficient correlation of 0.94.
    Bioorganic & Medicinal Chemistry 06/2003; 11(10):2293-9. · 2.90 Impact Factor
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    ABSTRACT: Hydroxypropyl-beta-cyclodextrin (HPBCD) was investigated as a possible solubilizer for a series of poorly water-soluble antimalarial drugs. The solubilities of artemisinin, artether, dihydroartemisinin, and 10-deoxoartemisinin in HPBCD solutions were studied. The phase-solubility profile of these drugs in HPBCD solutions, in the concentration range studied, can be classified as type A(L) or soluble 1:1 complexes. The solubilities of artemisinin, artether, dihydroartemisinin, and 10-deoxoartemisinin in 20% w/v solutions of HPBCD are 4.5, 1.3, 6.0, and 5.2 mg/mL, respectively. The stability constants of artemisinin, dihydroartemisinin, artether, and 10-deoxoartemisinin complexes with HPBCD are 475, 405, 327, and 146 M(-1), respectively. Three different docking methods, SYBYL DOCK, FlexiDock, and DOCK 4.0.1 were evaluated to further understand the complexation modes and applicability of the docking programs for the modeling of inclusion complexes. The results showed that DOCK 4.0.1 offers a better correlation in terms of orientation of molecules inside the cyclodextrin cavity and also in terms of docking scores.
    Journal of Pharmaceutical Sciences 04/2003; 92(3):649-55. · 3.13 Impact Factor
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    ABSTRACT: Increasing resistance of malaria parasites to conventional antimalarial drugs is an important factor contributing to the persistence of the disease as a major health threat. The ongoing search for novel targets has resulted in identification and expression of several enzymes including cysteine proteases that are implicated in hemoglobin degradation. Falcipain-2 and falcipain-3 are considered to be the two principal cysteine proteases in this degradation, and hence, are potential drug targets. A homology model of falcipain-3 was built and validated by various structure/geometry verification tools as well as docking studies of known substrates. The correlation coefficient of 0.975 between interaction energies and K(m) values of these substrates provided additional support for the model. On comparison with the previously reported falcipain-2 homology model, the currently constructed falcipain-3 structure showed important differences between the S2 pockets that might explain the variations in the K(m) values of various substrates for these enzymes. Further, docking studies also provided insight into possible binding modes and interactions of ligands with falcipain-3. Results of the current study could be employed in de novo drug design leading to development of new antimalarial agents.
    Protein Science 04/2003; 12(3):501-9. · 2.74 Impact Factor
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    ABSTRACT: Increasing resistance of malaria parasites, in particular Plasmodium falciparum, demands a serious search for novel targets. Cysteine protease in P. falciparum, encoded by a previously unidentified gene falcipain 2, provides one such target to design chemotherapeutic agents for treatment of malaria. In fact, a few cysteine protease inhibitors have been shown to inhibit growth of cultured malarial parasites. In absence of a crystal structure for this enzyme, homology modeling proved to be a reasonable alternative to study binding requirements of the enzyme. A homology model for falcipain 2 was developed and validated by docking of known vinyl sulfone inhibitors. Further, based on the observations of these studies, novel isoquinoline inhibitors were designed and synthesized, which exhibited in vitro enzyme inhibition at micromolar concentrations.
    Journal of biomolecular Structure & Dynamics 05/2002; 19(5):765-74. · 2.98 Impact Factor
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    ABSTRACT: Artemisinin (1) is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua L. Because of the effectiveness of Artemisinin in the treatment of drug-resistant Plasmodium falciparum and its rapid clearance of cerebral malaria, development of clinically useful semisynthetic drugs for severe and complicated malaria (artemether, artesunate) was prompt. However, recent reports of fatal neurotoxicity in animals with dihydroartemisinin derivatives such as artemether have spawned a renewed effort to develop nontoxic analogues of artemisinin. In our effort to develop more potent, less neurotoxic agents for the oral treatment of drug-resistant malaria, we utilized comparative molecular field analysis (CoMFA) and hologram QSAR (HQSAR), beginning with a series of 211 artemisinin analogues with known in vitro antimalarial activity. CoMFA models were based on two conformational hypotheses: (a) that the X-ray structure of artemisinin represents the bioactive shape of the molecule or (b) that the hemin-docked conformation is the bioactive form of the drug. In addition, we examined the effect of inclusion or exclusion of racemates in the partial least squares (pls) analysis. Databases derived from the original 211 were split into chiral (n = 157), achiral (n = 34), and mixed databases (n = 191) after leaving out a test set of 20 compounds. HQSAR and CoMFA models were compared in terms of their potential to generate robust QSAR models. The r(2) and q(2) (cross-validated r(2)) were used to assess the statistical quality of our models. Another statistical parameter, the ratio of the standard error to the activity range (s/AR), was also generated. CoMFA and HQSAR models were developed having statistically excellent properties, which also possessed good predictive ability for test set compounds. The best model was obtained when racemates were excluded from QSAR analysis. Thus, CoMFA of the n = 157 database gave excellent predictions with outstanding statistical properties. HQSAR did an outstanding job in statistical analysis and also handled predictions well.
    Journal of Medicinal Chemistry 02/2002; 45(2):292-303. · 5.61 Impact Factor
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    ABSTRACT: Sarcophine (1) is a furanocembranoid diterpene first reported from the Red Sea soft coral Sarcophyton glaucum with remarkable yields of up to 3% dry weight. Semisynthetic transformation of the lactone to lactam in sarcophine by reaction with benzyl and ethylamine afforded six new N-substituted azasarcophines (2–7), in addition to an asymmetric novel dimer 8. The in vitro activity of azasarcophines against Palsmodium falciparium (D6 clone) and P. falciparium (W2 clone) are also discussed.
    Tetrahedron 01/2002; 58(19):3699-3708. · 2.80 Impact Factor
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    ABSTRACT: INTRODUCTION The hepatitis C virus (HCV) is a major health problem afflicting millions of people worldwide. Current therapies suffer from low efficacy and several side effects. New antiviral targets are emerging, among these the NS3 protease. This serine protease is responsible for viral polyprotein processing and hence essential for HCV replication. Today, proof-of-concept for the first protease inhibitor in humans has been established by researchers at Boehringer Ingelheim. 1 Product-based inhibitors with a C-terminal carboxylic acid have proven to be both potent and selective inhibitors of the NS3 protease. Our group recently published the successful bioisosteric replacement of this carboxylic acid with the acidic phenyl acyl sulfonamide functionality on hexa-and pentapeptides. 2 Encouraged by our previous results we herein present a more detailed investigation of the acyl sulfonamide functionality on both tetra-and tripeptides. N O H N R O NH O O O N O Compd R Ki ± SD (µM) a Compd R Ki ± SD (µM) a 3 OH O 0.76 ± 0.1 K i (µM) ± SD a a Measured in an enzymatic assay comprising the full-length NS3 protein. TRIPEPTIDES Next, the effect from the acyl sulfonamide functionality atoms and its substituent (prime side) on inhibitory potency was studied. A tripeptide structure, elegantly designed by researchers at Boehringer Ingelheim, was chosen as scaffold (Table 2). K i -values of 3-8 demonstrates that prime side interactions are involved in binding of the inhibitors and K i -values of 9-11 indicate the importance of the sulfonyl oxygens as well as the acidic property of the acyl sulfonamide. TETRAPEPTIDES Initially, the phenyl acyl sulfonamide functionality was evaluated on two different tetrapeptide sequences (1a-b, 2a-b (Table 1)). Similar results as for previous reported hexa-and pentapeptides were obtained with the acyl sulfonamides being approximately 5 times more active than the corresponding carboxylic acids. 2 a Measured in an enzymatic assay comprising the full-length NS3 protein. b Measured in a cell-based HCV replicon assay. Table 3 CONCLUSIONS An extensive study of the acyl sulfonamide functionality as a carboxylic acid replacement in HCV NS3 protease inhibitors has been carried out. Compared to carboxylic acids the acyl sulfonamide functionality show superior properties both in terms of enzymatic and cellular activitiy. Sulfonyl oxygens, prime side substituent and the acidic property of acyl sulfonamides contribute to inhibitory potency. The P1 amino acid greatly affects the increase in activity of acyl sulfonamides compared to carboxylic acids. Finally, the influence of the P1 amino acid on inhibitory activity was investigated (Table 3). As can be seen from compounds 3 and 6, the increase in activity changing from a carboxylic acid to a phenyl acyl sulfonamide was not as great as for the tetrapeptides. However, when substituting the moderate P1 norvaline to a more optimized P1 amino acid 4 a remarkable increase in activity was observed (12-15) indicating a more optimal binding in the latter case. Another important finding is that the acyl sulfonamides also show superior activities compared to the carboxylic acids in a cell-based assay (HCV replicon).

Publication Stats

193 Citations
44.23 Total Impact Points

Institutions

  • 2003
    • Central Drug Research Institute
      Lakhnau, Uttar Pradesh, India
  • 2002–2003
    • University of Mississippi
      • Department of Medicinal Chemistry
      Oxford, MS, United States