Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2 CourniaBiomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiov,1 752/ Athens, Greece7.1IntroductionI he drug design process is unequivocally a Lime-consuming and expensive endeavor, with recent estimates classifying it as a $2.6 billion expenditure [11. From target identification and Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2 validation, to hit-and-lead discovery, as well as lead optimization, preciinical and clinical, the outlay in each consecutive stage accounts for seveEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
ral millions of US dollars, with the financial burden surging with every unsuccessful attempt, especially in the late phases of the development. Fortu163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2 analysis, held the basis of systematic efforts targeting the efficacious treatment of protein-provoking diseases [2J. In addition, the advances in high-throughput screening (I ITS) experiments allowed the assessment of thousands of molecules concurrently by employing robotic automation, diminished Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2the human labor, and dominated the area of hit identification in the past two decades [3j.Nonetheless, H I S is still Lime consuming and expensive, wiEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
th its acquisition value and operational costs being prohibitive for most laboratories. Moreover, careful decision making to decrease attrition rates 163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2gn ((.’ADD). Molecular modeling techniques have revolutionized the conventional drug discovery processes, by enabling the reduction of time and resources allocated in the hit identification, hit-to-lead optimization and lead optimization phases of the drug discovery pipeline. Novel druglike candidat Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2es are first examined in silica for their expected affinity to a therapeutic target (in the case of structure-based drug design) or their similarity tEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
o previously identified active compounds (ligand-based drug design), as well as the prediction of physicochemical properties with the aid of sophistic163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2 prioritizing organic synthesis efforts [4]. Excluding drug candidates bearing no chance of demonstrating success early in the process can thus eliminate the substantial cost that derives from failures.Biomolectilar Simulations in Structure- Based Drug Discovery,First Edition. Edited by Francesco L. Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2 Gervasio and Vojtech Spiwok.© 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA.166 I 7 From Computers to BedEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
side: Computational Chemistry Contributing to FDA ApprovalHie extensive and systematic use of computer-assisted methods became feasible only in the pa163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2ntensified in the past decade due to the rapid development of faster architectures in tandem with the arrival of graphical processing unit (GPU) coding [5], the improvement of methodologies in both theoretical and application levels [6, 7], as well as better algorithms enabling more accurate atomist Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2ic description and treatment of interactions that new force fields provide [8-101- Moreover, problems related to poor sampling and difficult}' in surpEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
assing energetic barriers have been addressed with pioneering enhanced sampling techniques [11-131- Reviews thoroughly describing recent computer-aide163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2ably linked with drug design-oriented attempts.Ulis trend has not been unnoticed by pharmaceutical companies, which have reformed the structure of their R&D departments by incorporating CADD laboratories active in the development process. GlaxoSmithKline, one of the companies that has adopted CADI) Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2methods, contends that “design” rather than “discovery” is its primary goal, explaining thal medicinal chemists exploit the maximum potential by applyEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
ing true design principles [18]. On lhe same issue, Merck, Janssen, Vertex Pharmaceuticals, and other smaller companies discuss the involvement of CAD163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2onal techniques can be a powerful lool in the discovery of new medicaments. But to what extent has a computational procedure ever successfully guided this complex procedure, leading to a safe and effective drug that is currently on the market? In the current review, we present cases of the US Food a Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2nd Drug Administration (FDA)-approved drugs for the discovery of which CADD techniques played an instrumental role. This includes either strategies thEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
at were entirely dependent and guided by computational analyses results or workflows, where a computational method was selectively utilized at a speci163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2ery Process:Early DaysCADD is intrinsically based on the rational design of drugs. Rational drug design pertains to the development of drugs with favorable structural characteristics according to the three-dimensional structure of the disease target, which is usually a protein, when the structure of Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2 the target is unknown, rational drug design proceeds by examining molecules chemically similar to already known active compounds. The concept of ratiEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
onal drug discovery is not new and does not necessarily require the use of computers. Decades ago, medicinal chemists understood its benefits, long be163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2ples of the first FDA-approved drugs, which were developed using rational design, illustrate the significant role of the latter in the discovery of potent and efficient drugs.7.2.1Captopril (Capoten®)Angiotensin-converting enzyme (ACE) is a key component of the reninangiotensin system and a pharmaco Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2logical target for hypertension [22]. Captopril is the first oral ACE inhibitor and its discovery was considered a breakthrough at that time, not onlyEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
in management of blood pressure but also because it was one of the first drugs developed with rational drug design [23]. At the time of the discovery163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2for which more structural data was available [24]. In 1973, Byers and Wolfenden identified a potent inhibitor of car boxy peptidase A, the D-benzylsuccinic acid [25]. '1 his data led Ondelli and Cushman to the assumption that the active site of ACE would be similar to that of carboxypeplidase A and Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2that a potent inhibitor of ACE would be also similar to that of D-benzylsuccinic acid. In 1977, they published the results of their study according toEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
which they had developed a theoretical model of the active site of ACE based on that of carboxypeptida.se A, concomitantly taking into consideration 163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2ypeptidasc A melalloprolein, a positively charged group able to form ionic bonds with the terminal carboxyl groups of the substrates and a group capable of hydrogen bonding to interact with the COOI I-terminal amide bond of the substrate. These three features were in agreement with the structure of Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2the D-benzylsuccinic acid inhibitor ofcarboxypeptida.se A, with the only difference that instead of a hydrogen-bonding able group, the inhibitor had aEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
hydrophobic group as the substrate of carboxypeptidasc A did. Hie next step was to modify appropriately this inhibitor in order to better fit to the 163PartinApplications and Success Stories7From Computers to Bedside: Computational Chemistry Contributing to FDA ApprovalChristina Athanasiou and Zoe Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2om and the cationic site should be greater than that in carboxypeptidase A. Thus, they replaced succinic acid with a longer succinyl derivative of an aminoacid, succinyl-L-proline. In addition, they replaced the zinc-intcracting carboxyl group of D-bcnzylsuccinic acid with a mercapto group, which si Ebook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2gnificantly increased the potency. Subsequent alterations in the structure of the compound led eventually to captopril. FDA approval came in 1981 andEbook Biomolecular simulations in structure-based drug discovery (Vol 75): Part 2
it was marketed by Bristol-Myers Squibb as an anti-hypertensive.7.2.2Saquinavir (Invlrase®)Human immunodeficiency virus-1 protease (1IIV-1 PR) plays aGọi ngay
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