Vaishali M. Patil

Current perspective of HCV NS5B inhibitors: a review.

Hepatitis C virus (HCV) infection has emerged as one of the most significant disease to affect humans. Despite its large medical and economical impact, there are no vaccines or efficient therapies without major side effects. The HCV non-structural protein 5B (NS5B) is the RNA-dependent RNA polymerase responsible for the complete copy of the RNA viral genome and is a target of choice for the development of anti-HCV drugs. Although many small molecules have been identified as allosteric inhibitors of NS5B, very few are active in clinical applications. Developments in the field have prompted us to review the research work on HCV NS5B polymerase inhibitors, especially their structure activity relationships and molecular modeling studies. This review will focus on the journey of drug discovery of HCV NS5B inhibitors covering both nucleoside and non-nucleosides.

Synthesis, in vitro and in silico NS5B polymerase inhibitory activity of benzimidazole derivatives.

Hepatitis C virus (HCV) NS5B polymerase is the key replicating protein of the virus and thus an attractive target for drug development. Here we report on the synthesis and biological evaluation of a new series of benzimidazole derivatives as HCV NS5B inhibitors. This yielded compound 6b and 6d bearing 2-(2-benzyloxy)phenyl and 2-(4-methylbenzyloxy)phenyl moieties, respectively, as promising leads. Binding mode of compound 6d in allosteric pocket (AP)-1 of NS5B will form the basis for future structure-activity relationship optimization.

3D QSAR kNN-MFA studies on thiouracil derivatives as hepatitis C virus inhibitors

The development of new therapies to treat hepatitis C virus (HCV) infection effectively is currently an intensive area of research. To achieve this objective quantitative structure–activity relationship (QSAR) study was carried as it provides the rationale for the changes in the structure to have more potent analogs. In this article, we report 3D QSAR studies for the set of 50 HCV NS5B RNA-dependent RNA polymerase inhibitors using k-Nearest Neighbor Molecular Field Analysis (kNN-MFA) method combined with various selection procedures. By using kNN-MFA approach, various 3D QSAR models were generated to study the effect of steric and electrostatic descriptors on anti-HCV activity. The model with good external and internal predictivity for the training and test set has shown cross validation (q2) and external validation (pred_r2) values of 0.85 and 0.75, respectively. The steric descriptors at the grid points S_430, S_1065, and S_1165 play an important role in the design of new molecule. It also suggests the importance of aromatic or large bulky ring substituent at R1 to increase the HCV inhibitory activity as well as large bulky substituent at R2 reduces activity. This model was found to yield reliable clues for further optimization of thiouracil derivatives in the data set.

3D-QSAR and Docking Studies on a Series of Benzothiadiazine Derivatives as Genotype 1 HCV Polymerase Inhibitors

The Benzothiadiazine derivatives have been regarded as a novel class of HCV genotype 1 polymerase inhibitors. To explore the relationship between the structures of substituted Benzothiadiazine derivatives and their inhibitory activities against HCV, 3D-QSAR and molecular docking studies were performed on a dataset of ninty-eight compounds. The 3D-QSAR models resulted from seventy-eight molecules in the training set gave q(2) value of 0.81 and a test set of twenty compounds, gave predictive r(2) value of 0.94. 3D-QSAR model generated from kNN-MFA along with the docking binding structures provided enough information about the structural requirements for better activity. The results can serve as a useful guideline to design novel HCV genotype 1 inhibitors with better potencies.

HCV Inhibitors: Role of Compounds from Botanical Sources.

The developing number of hepatitis C virus infected cases worldwide has threatened peoples health. The available therapeutic options have low specificity, side effects and high rate of drug resistance and thus potentiate the need for novel effective anti-HCV drugs. Agents obtained from natural sources offer an enormous scope of structural diversity and broad therapeutic range of coverage. This review summarizes the research and development of anti-HCV agents (plant extracts/isolated components) obtained from various natural sources along with the associated mechanism of HCV inhibition. Some of the reported examples include triterpenes, naringenin, Proanthocyanidin, curcumin, Epigallocatechin-3-gallate, quercetin and abrogates having diverse anti-HCV properties. The compiled knowledge regarding anti-HCV agents from natural sources will provide considerable information for developing novel safe and effective anti-HCV drugs.

Heterocyclic Secretase Inhibitors for the Treatment of Alzheimer’s Disease: An Overview

Alzheimers disease (AD), the most common neurodegenerative disorder and demands to find a way for prevention and delayed onset. The development of therapeutics for AD is based on the amyloid cascade hypothesis (vaccines, β- and γ-Secretase inhibitors), or targeting tau and neurofibrillary tangle formation, neuroinflammation, etc. Cholinesterase, BACE-1, amyloid-β 1-42, γ and β-Secretase, Phosphodiesterase type IV (PDE4) inhibitors are the reported treatment strategies. Among these, the γ- and β-Secretase inhibitors can be clustered in several heterocyclic classes (imidazoles, thiazoles, indoles, benzaldehydes, pyrimidine, etc), with subsequent description of the structure-activity relationships, and extended to the pharmacological profile in order to evaluate their drug-likeness, with special attention to toxicity and bioavailability. This article discusses the approaches proposed by several research groups working on the synthesis of enzyme inhibitors, based on modelling studies and the way these findings were used to obtain new drugs for the treatment of AD.

GENIUS In Silico Screening Technology for HCV Drug Discovery

The various reported in silico screening protocols such as molecular docking are associated with various drawbacks as well as benefits. In molecular docking, on interaction with ligand, the protein or receptor molecule gets activated by adopting conformational changes. These conformational changes cannot be utilized to predict the 3D structure of a protein-ligand complex from unbound protein conformations rigid docking, which necessitates the demand for understanding protein flexibility. Therefore, efficiency and accuracy of docking should be achieved and various available/developed protocols may be adopted. One such protocol is GENIUS induced-fit docking and it is used effectively for the development of anti-HCV NS3-4A serine protease inhibitors. The present review elaborates the GENIUS docking protocol along with its benefits and drawbacks.

Anticancer Potential of Flavonoids: Chemistry, Biological Activities, and Future Perspectives

Abstract The polyphenolic flavonoids are found ubiquitously in plants. Flavonoids are nontoxic and possess a remarkable spectrum of biological activities such as antiallergic, antiinflammatory, antioxidant, antimutagenic, anticarcinogenic, and modulation of enzymatic activities. Some of the reported flavonoids are able to influence the deregulated processes during cancer development. Thus, flavonoids have beneficial effects on health and have the potential for the development of possible chemoprotective therapeutic agents for the treatment of cancer. Some dietary flavonoids have antitumor activity during in vivo studies and also repress angiogenesis. In vitro studies conclude the potential of flavonoid-induced modulation of kinases with apoptosis, vascularization, cell differentiation, cell proliferation, etc. The results obtained from the laboratory and epidemiological studies have confirmed the potential of flavonoids and have stimulated the development of flavonoids. Most of the available chemotherapeutic agents have a major obstacle as they do not spare normal cells and the development of multidrug resistance. The promising results stimulate the development of flavonoids and their synthetic analogs for cancer prevention and chemotherapy. This chapter covers the structural characteristics of flavonoids, their role in cancer treatment and prevention in in vitro cell lines and in vivo murine models, and the human clinical trials.

Structural Flexibility in HCV NS5B Polymerase and Molecular Modelling of Anti-HCV Drugs

Background: NS5B polymerase remains an important anti-hepatitis C virus (HCV) drug target. It has been well reported that ligand binding induces large conformational changes in the receptor. Several computational models describing polymerase dynamics have been reported. Various conformational forms have been determined by crystallography and NMR experiments and they suggest the binding of HCV inhibitors in allosteric sites might affect polymerase flexibility. Objective: In most of the cases of structure-based drug design (SBDD), only static structures have been given consideration and most molecular modeling studies have recognized the importance of flexibility. The standard virtual docking methods using rigid receptor may give misleading results as in reality many proteins undergo side-chain and/or backbone movements. The importance of HCV NS5B polymerase receptor flexibility in altering the binding site to complement the shape and binding mode of the ligand i.e. induced fit docking need to be considered. Method: The various methodologies were adopted for molecular modeling based on induced-fit docking at the well-defined inhibitor binding sites i.e. “palm” and “thumb” domain. Some of the well reported NNIs and NIs are VX-222, ANA598/Setrobuvir, CS01, aureusidin, N,N-disubstituted phenylalanine, benzothiadiazine, 6-aminoquinoline derivatives, etc. Results: These assumptions have lead to application of quantum mechanics and induced-fit docking for the development of various HCV NS5B polymerase inhibitors. This enzyme has proved to be challenging and therefore potential ligands with structural diversity have been modified to enhance selectivity and affinity. The flexible nature of HCV polymerase, reveals details about substrate-inhibitor interaction to its active site within the membrane. Conclusion: It will help to develop allosteric inhibitors into efficient drugs by understanding their indirect mode of action and complex structure-activity/kinetic relationship. A R T I C L E H I S T O R Y Received: June 12, 2017 Revised: September 13, 2017 Accepted: April 05, 2018

Applications of Structure Based Drug Design Approaches towards Design and Development of Calcium Channel Blockers

Structure-Based Drug Discovery approaches facilitate the efforts towards drug discovery and in this communication these are applied towards development of Calcium Channel Blockers (CCBs). Quantitative structure-activity relationship (QSAR) studies were carried out on a series of 1,3-dioxoisoindoline-5-carboxamide derivatives and the contributing descriptors were identified as hydrophobicity, electronic constant (σR1) and some indicator parameter (I). The data set designed based on QSAR conclusions was screened against Voltage gated CCB receptor and the binding profile was predicted.