Advances in structure-based drug design

Abstract

Over the past two decades, technological advancements in experimental methods such as NMR and X-ray crystallography have allowed structure-based drug design (SBDD) to obtain a vital position in medicinal chemistry. Owing to the dramatic increase in the availability of 3D structure of protein targets and the rapid advancement in computational chemistry, SBDD has become an integral strategy for both lead generation and lead optimization. In addition, computer-aided molecular docking has some significant advantages over traditional high-throughput screening (HTS). Medicinal chemists now have access to structural information on small molecule candidates bound to the therapeutic target within days of compound synthesis. SBDD permits the creation of new ligands with stepwise assembly of atoms or molecular fragments that conform to the binding pocket. This ability to generate novel structures not found in any database has cemented SBDD a crucial method for modern drug discovery.In this special issue of Trends in Pharmacological Sciences, experts from academia and industry discuss some of the general principles of structure-guided drug discovery, as well as share diverse experiences from their laboratories. We highlight the excitement that novel GPCR crystal structures have brought to the field, and feature numerous SBDD success stories, including developmental case histories of compounds that have recently reached the clinic.The use of smaller molecules or fragments in the drug discovery process has led to success in delivering novel leads for many different targets. Chris Murray, Marcel L Verdonk, and David C Rees present three recent successful case histories in fragment-based drug design (FBDD). They re-examine the key concepts and challenges of FBDD, with particular emphasis on recent literature and their own experience with FBDD applications. Later in the issue, Jubb and colleagues examine targeting of protein-protein interfaces PPIs of multiprotein complexes that mediate cell regulation, long regarded by many as undruggable. Targeting of PPIs is now becoming possible, in part though exploitation of “hotspots” that contribute much of the free energy of interaction.Wasserman and colleagues discuss their experiences in using Synchrotron X-ray sources for SBDD. Synchrotron sources offer access to a continuous range of X-ray energies, and determination of a new protein structure via direct measurement of X-ray phases can often be accomplished with just one crystal.Two articles tackle the exciting possibilities raised by recently solved crystal structures of GPCRs. The hope is that these structures will permit the same type of successful rational drug design for GPCRs as has already been seen with soluble targets. Mason and colleagues discuss how the differences in the calculated properties (lipophilicity, hydrogen-bonding etc.) and observed receptor conformations between the GPCR antagonist and agonist protein structures yields important pointers for rational drug design and a better understanding of GPCR activation. In a related article, Brian Shoichet and Brian Kobilka highlight the potential of in silico docking for designing molecules that bind to GPCRs. Early studies suggest that GPCR binding pockets are well suited to docking, and docking screens have identified potent and novel compounds for these targets.We also highlights some recent success stories in SBDD. Blocking Beta-secretase 1 (BACE1) function could be an effective strategy to combat Alzheimer's disease, but developing a brain-penetrant BACE1 inhibitor has proved challenging. Zhaoning Zhu discusses how SBDD the iminoheterocycle class of BACE1 inhibitors solved this crucial issue, and provides lessons that should be applicable to other aspartyl proteases of therapeutic importance. In addition, Richard Norman, Dorin Toader and Andrew Ferguson discuss the ways in which SBDD can be used to obtain kinase selectivity. They review SBDD of several molecules which are currently in clinical trials, including the cMet inhibitor ARQ 197 and the Bcr-Abl inhibitor ponatinib.SBDD has also proved crucial in the development of several compounds that have recently reached the market. In 2008, the direct thrombin inhibitor dabigatran etexilate (Pradaxa®) developed by Boehringer Ingelheim became the first novel antithrombotic molecular entity to enter the market in 50 years. Herbert Nar discusses how the 3D structures of the targets thrombin and factor Xa helped guide the development of this compound. In a separate article, Srikanth Venkatraman describes the use of SBDD in the discovery of boceprevir (Victrelis®), a first-in-class new drug that significantly improves the cure rate for patients infected with hepatitis C.Trends in Pharmacological Sciences would like to thank all of the contributors and especially our guest Editor, Miles Congreve, for their tremendous efforts in pulling this special issue together. We hope our readers enjoy the articles, and come away excited by the many roles that structure can play in development of new and safer drugs. Over the past two decades, technological advancements in experimental methods such as NMR and X-ray crystallography have allowed structure-based drug design (SBDD) to obtain a vital position in medicinal chemistry. Owing to the dramatic increase in the availability of 3D structure of protein targets and the rapid advancement in computational chemistry, SBDD has become an integral strategy for both lead generation and lead optimization. In addition, computer-aided molecular docking has some significant advantages over traditional high-throughput screening (HTS). Medicinal chemists now have access to structural information on small molecule candidates bound to the therapeutic target within days of compound synthesis. SBDD permits the creation of new ligands with stepwise assembly of atoms or molecular fragments that conform to the binding pocket. This ability to generate novel structures not found in any database has cemented SBDD a crucial method for modern drug discovery. In this special issue of Trends in Pharmacological Sciences, experts from academia and industry discuss some of the general principles of structure-guided drug discovery, as well as share diverse experiences from their laboratories. We highlight the excitement that novel GPCR crystal structures have brought to the field, and feature numerous SBDD success stories, including developmental case histories of compounds that have recently reached the clinic. The use of smaller molecules or fragments in the drug discovery process has led to success in delivering novel leads for many different targets. Chris Murray, Marcel L Verdonk, and David C Rees present three recent successful case histories in fragment-based drug design (FBDD). They re-examine the key concepts and challenges of FBDD, with particular emphasis on recent literature and their own experience with FBDD applications. Later in the issue, Jubb and colleagues examine targeting of protein-protein interfaces PPIs of multiprotein complexes that mediate cell regulation, long regarded by many as undruggable. Targeting of PPIs is now becoming possible, in part though exploitation of “hotspots” that contribute much of the free energy of interaction. Wasserman and colleagues discuss their experiences in using Synchrotron X-ray sources for SBDD. Synchrotron sources offer access to a continuous range of X-ray energies, and determination of a new protein structure via direct measurement of X-ray phases can often be accomplished with just one crystal. Two articles tackle the exciting possibilities raised by recently solved crystal structures of GPCRs. The hope is that these structures will permit the same type of successful rational drug design for GPCRs as has already been seen with soluble targets. Mason and colleagues discuss how the differences in the calculated properties (lipophilicity, hydrogen-bonding etc.) and observed receptor conformations between the GPCR antagonist and agonist protein structures yields important pointers for rational drug design and a better understanding of GPCR activation. In a related article, Brian Shoichet and Brian Kobilka highlight the potential of in silico docking for designing molecules that bind to GPCRs. Early studies suggest that GPCR binding pockets are well suited to docking, and docking screens have identified potent and novel compounds for these targets. We also highlights some recent success stories in SBDD. Blocking Beta-secretase 1 (BACE1) function could be an effective strategy to combat Alzheimer's disease, but developing a brain-penetrant BACE1 inhibitor has proved challenging. Zhaoning Zhu discusses how SBDD the iminoheterocycle class of BACE1 inhibitors solved this crucial issue, and provides lessons that should be applicable to other aspartyl proteases of therapeutic importance. In addition, Richard Norman, Dorin Toader and Andrew Ferguson discuss the ways in which SBDD can be used to obtain kinase selectivity. They review SBDD of several molecules which are currently in clinical trials, including the cMet inhibitor ARQ 197 and the Bcr-Abl inhibitor ponatinib. SBDD has also proved crucial in the development of several compounds that have recently reached the market. In 2008, the direct thrombin inhibitor dabigatran etexilate (Pradaxa®) developed by Boehringer Ingelheim became the first novel antithrombotic molecular entity to enter the market in 50 years. Herbert Nar discusses how the 3D structures of the targets thrombin and factor Xa helped guide the development of this compound. In a separate article, Srikanth Venkatraman describes the use of SBDD in the discovery of boceprevir (Victrelis®), a first-in-class new drug that significantly improves the cure rate for patients infected with hepatitis C. Trends in Pharmacological Sciences would like to thank all of the contributors and especially our guest Editor, Miles Congreve, for their tremendous efforts in pulling this special issue together. We hope our readers enjoy the articles, and come away excited by the many roles that structure can play in development of new and safer drugs.