Review on chemogenomic approaches towards hepatitis C viral targets

Venkatesan, Arthi; J, Febin Prabhu Dass

doi:10.1002/jcb.28581

Cited by 4 publications

(4 citation statements)

References 120 publications

(239 reference statements)

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“…Pharmacophore‐based studies followed by virtual screening and hit optimizations on these allosteric sites yielded potent ligands able to inhibit the function of RdRp‐NS5B allosterically 344,345 . We refer the readers to a recent review that summarizes the structure‐based and ligand‐based drug development against RdRp‐NS5B along with other nonstructural proteins of HCV 346 …”

Section: Rational Allosteric Drug Designmentioning

confidence: 99%

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Rational design of allosteric modulators: Challenges and successes

Chatzigoulas

Cournia

2021

WIREs Comput Mol Sci

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Recent advances in structural biology and computational techniques have revealed allosteric mechanisms for an abundance of targets leading to the establishment of rational design of allosteric modulators as a new avenue for drug discovery. Considering that allostery is an intrinsic property of the protein conformational ensemble, allosteric drug design has the potential to develop into an innovative approach to modulate the dysregulation of therapeutic targets that are considered to be undruggable at their orthosteric site, explore strategic design opportunities to tackle new chemical space, or develop mutant-specific therapies to target mutations occurring far from the enzyme active site. Traditionally, allosteric drug discovery has been performed through high-throughput screening or through serendipitous discoveries; however, recent developments in structure-based and ligand-based methods have led to exciting advancements of designing bioactive allosteric ligands rationally. In this review article, we highlight the advantages and disadvantages of allosteric modulators and present structure-based and ligand-based drug design methodologies for the identification of allosteric binding sites and allosteric modulators. We also illustrate representative studies for allosteric modulators design for proteins belonging to a wide range of protein families, also considering irreversible binding with covalent allosteric modulators. Additionally, we analyze challenges and successes in the rational design of allosteric inhibitors and activators. Finally, we present the future of rational allosteric ligand design with newly built computational tools that we expect to be applied in future studies, concluding to theoretical and practical guidelines for allosteric ligand design strategies and identify knowledge gaps that need to be addressed to improve efficiency in allosteric drug design.

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Section: Rational Allosteric Drug Designmentioning

confidence: 99%

“…344,345 We refer the readers to a recent review that summarizes the structure-based and ligand-based drug development against RdRp-NS5B along with other nonstructural proteins of HCV. 346…”

Section: Hcv Nonstructural Protein 5bmentioning

confidence: 99%

Rational design of allosteric modulators: Challenges and successes

Chatzigoulas

Cournia

2021

WIREs Comput Mol Sci

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“…For the past two decades, the standard therapy for HCV infection has been based on peginterferon and the antiviral nucleoside analog ribavirin. To date, approximately half of patients achieved a lower sustained virologic response (SVR) and suffered from undesired harmful effects such as cardiac-related problems, leukopenia, and thrombocytopenia [6]. Recently, many directacting antiviral (DAA) drugs have been authorized for the treatment of HCV infection with higher SVR rates (>90%), shorter duration, and fewer adverse effects compared with older treatment therapies [7,8].…”

Section: Introductionmentioning

confidence: 99%

Monte Carlo Method and GA-MLR-Based QSAR Modeling of NS5A Inhibitors against the Hepatitis C Virus

et al. 2022

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Hepatitis C virus (HCV) is a serious disease that threatens human health. Despite consistent efforts to inhibit the virus, it has infected more than 58 million people, with 300,000 deaths per year. The HCV nonstructural protein NS5A plays a critical role in the viral life cycle, as it is a major contributor to the viral replication and assembly processes. Therefore, its importance is evident in all currently approved HCV combination treatments. The present study identifies new potential compounds for possible medical use against HCV using the quantitative structure–activity relationship (QSAR). In this context, a set of 36 NS5A inhibitors was used to build QSAR models using genetic algorithm multiple linear regression (GA-MLR) and Monte Carlo optimization and were implemented in the software CORAL. The Monte Carlo method was used to build QSAR models using SMILES-based optimal descriptors. Four splits were performed and 24 QSAR models were developed and verified through internal and external validation. The model created for split 3 produced a higher value of the determination coefficients using the validation set (R2 = 0.991 and Q2 = 0.943). In addition, this model provides interesting information about the structural features responsible for the increase and decrease of inhibitory activity, which were used to develop eight novel NS5A inhibitors. The constructed GA-MLR model with satisfactory statistical parameters (R2 = 0.915 and Q2 = 0.941) confirmed the predicted inhibitory activity for these compounds. The Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADMET) predictions showed that the newly designed compounds were nontoxic and exhibited acceptable pharmacological properties. These results could accelerate the process of discovering new drugs against HCV.

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“…With high genetic variability and different geographical distribution, HCV are classified into seven main genotypes (GT1-7), most of which have multiple subtypes (a, b, and so on) [14] , [15] , [16] . The genome of HCV containing approximately 9600 nucleotides can translate to a single open reading frame (ORF) flanked by the 5′- and 3′-untranslated regions (UTR) [17] . The ORF can encode a single large polyprotein precursor which is ultimately cleaved to form ten proteins: three structural proteins (one nucleocapsid protein and two envelope proteins) and seven nonstructural proteins which include two proteins required for virion production (p7 and NS2) as well as five proteins that form the cytoplasmic viral replication complex (NS3, NS4A, NS4B, NS5A, and NS5B) [1] , [18] .…”

Section: Introductionmentioning

confidence: 99%