Frontiers in Computational Chemistry for Drug Discovery

Computational methods pervade almost all aspects of drug discovery [1-3]. Computer-assisted tools contribute to the decision-making process along the entire drug discovery pipeline, including the validation of suitable targets, high-throughput screening of molecular libraries, the optimization of lead compounds, and the balance between pharmacological potency and physico-chemical and pharmacokinetic properties. This tendency will be reinforced in the next few years due to the continued increases in computer power, and the elaboration of sophisticated algorithms to capture the physico-chemical principles that underlie the activity of drugs. This effort should enable drug discovery methodology to evolve from approximate to more rigorous methods. How should computational methods evolve to ameliorate the success of drug discovery? The answer to this question is related to the identification of the current limitations faced by computational algorithms to unveil the delicate balance between factors that determine both potency and ADMET (absorption, distribution, metabolism, excretion, and toxicology) properties of drug candidates

Structural basis of the selective activation of enzyme isoforms: Allosteric response to activators of b1- and b2-containing AMPK complexes

AMP-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 complexes, which exhibit notable differences in the sensitivity to allosteric activators. To shed light into the molecular determinants of the allosteric regulation of this energy sensor, we have examined the structural and dynamical properties of β1- and β2-containing AMPK complexes formed with small molecule activators A-769662 and SC4, and dissected the mechanical response leading to active-like enzyme conformations through the analysis of interaction networks between structural domains. The results reveal the mechanical sensitivity of the α2β1 complex, in contrast with a larger resilience of the α2β2 species, especially regarding modulation by A-769662. Furthermore, binding of activators to α2β1 consistently promotes the pre-organization of the ATP-binding site, favoring the adoption of activated states of the enzyme. These findings are discussed in light of the changes in the residue content of β-subunit isoforms, particularly regarding the β1Asn111→β2Asp111 substitution as a key factor in modulating the mechanical sensitivity of β1- and β2-containing AMPK complexes. Our studies pave the way for the design of activators tailored for improving the therapeutic treatment of tissue-specific metabolic disorders

Dioxygen Binding and Sensing Proteins

Oxygen binding proteins (O2BIP) have been actively investigated over the last five decades due to their rich redox chemistry and function as O2 carriers in blood cells, as well as their function as gasotransmitters and sensors that modulate cellular signaling. A series of meetings on the periodic advances in the knowledge gained in the field of globin structure and function are conducted typically on a biannual basis. In the fall of 2018, the XXth International Conference was conducted, and very important papers with breakthrough discoveries were presented and very enthusiastically discussed. This was yet another highly successful meeting in the series. Select papers from this meeting were recently reviewed, updated and published over several issues of Antioxidants and Redox Signaling (ARS), as forum papers communicating the latest advances in this important area of redox biology. This forum editorial introduces these articles, and highlights their scientific significance in advancing the field. Each of these articles grew out of lectures presented in the meeting, and appears either as an original contribution or a comprehensive review in the journal. Overall, the articles published in the forum provide in-depth details on the recent developments in the field as well as point the way to future directions. These forum papers thus serve as an important summary of progress and the ongoing direction of this field, and serve to highlight recent advances in our understanding of O2BIP

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued e orts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature

From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus

With an estimated 1 billion people affected across the globe, influenza is one of the most serious health concerns worldwide. Therapeutic treatments have encompassed a number of key functional viral proteins, mainly focused on the M2 proton channel and neuraminidase. This review highlights the efforts spent in targeting the M2 proton channel, which mediates the proton transport toward the interior of the viral particle as a preliminary step leading to the release of the fusion peptide in hemagglutinin and the fusion of the viral and endosomal membranes. Besides the structural and mechanistic aspects of the M2 proton channel, attention is paid to the challenges posed by the development of efficient small molecule inhibitors and the evolution toward novel ligands and scaffolds motivated by the emergence of resistant strains

Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies

The pharmacophore concept is a fundamental cornerstone in drug discovery, playing a critical role in determining the success of in silico techniques, such as virtual screening and 3D-QSAR studies. The reliability of these approaches is influenced by the quality of the physicochemical descriptors used to characterize the chemical entities. In this context, a pivotal role is exerted by lipophilicity, which is a major contribution to host-guest interaction and ligand binding affinity. Several approaches have been undertaken to account for the descriptive and predictive capabilities of lipophilicity in 3D-QSAR modeling. Recent efforts encode the use of quantum mechanical-based descriptors derived from continuum solvation models, which open novel avenues for gaining insight into structure-activity relationships studies

Development of a Structure-Based, pH-Dependent Lipophilicity Scale of Amino Acids from Continuum Solvation Calculations

Lipophilicity is a fundamental property to characterize the structure and function of proteins, motivating the development of lipophilicity scales. Here we report a versatile strategy to derive a pH-adapted scale that relies on theoretical estimates of distribution coefficients from conformational ensembles of amino acids. This is accomplished by using an accurately parametrized version of the IEFPCM/MST continuum solvation model, as an effective way to describe the partitioning between n-octanol and water, in conjunction with a formalism that combines partition coefficients of neutral and ionic species of residues, and the corresponding pKa of ionizable groups. Two weighting schemes are considered to derive solvent-like and protein-like scales, which have been calibrated by comparison with other experimental scales developed in different chemical/biological environments and pH conditions, as well as by examining properties such as the retention time of small peptides and the recognition of antigenic peptides. A straightforward extension to nonstandard residues is enabled by this efficient methodological strategy

Ligand Binding Rate Constants in Heme Proteins Using Markov State Models and Molecular Dynamics Simulations

Computer simulation studies of the molecular basis for ligand migration in proteins allow the description and quantification of the key events implicated in this process as, such as the transition between docking sites, displacements of existing ligands and solvent molecules, and open/closure of specific 'gates', among other factors. In heme proteins, especially in globins, these phenomena are related to the regulation of protein function, since ligand migration from the solvent to the active site preludes ligand binding to the iron in the distal cavity, which in turn triggers the different globin functions. In this work, a combination of molecular dynamics simulations with a Markov-state model of ligand migration is used to the study the migration of O2 and ·NO in two truncated hemoglobins of Mycobacterium tuberculosis (truncated hemoglobin N -Mt-TrHbN- and O -Mt-TrHbO). The results indicate that the proposed model provides trends in kinetic association constants in agreement with experimental data. In particular, for Mt-TrHbN, we show that the difference in the association constant in the oxy and deoxy states relies mainly in the displacement of water molecules anchored in the distal cavity by O2 in the deoxy form, whereas the conformational transition of PheE15 between open and closed states plays a minor role. On the other hand, the results also show the relevant effect played by easily diffusive tunnels, as the ones present in Mt-TrHbN, compared to the more impeded passage in Mt-TrHbO, which contributes to justify the different .NO dioxygenation rates in these proteins. Altogether, the results in this work provide a valuable approach to study ligand migration in globins using molecular dynamics simulations and Markov-state model analysis

Understanding the mechanism of direct activation of AMP-kinase: Towards a fine allosteric tuning of the kinase activity

This research deals with the regulation of the AMPK activity by direct activators, such as compound A-769662. AMPK is a key enzyme to maintain the cellular energy homeostasis, as it regulates the levels of ATP, being an important target to metabolic diseases like obesity or diabetes MT2. It is formed by 3 subunits α, β, and γ. The activation mechanism of A-769662 is of particular interest, because it activates AMPK independently of α-Thr172 phosphorylation, the β-Ser108 being phosphorylated. Under these circumstances, binding of A-769662 enhances the AMPK activity up to >90-fold (PDB 4CFF) [1-3]. We have recently studied the chain of events implicated in the binding of this ligand to the activating binding site, which is located between the α and β subunits of AMPK. MD simulations of AMPK were run for apo, holo, and holo+ ATP systems. For each system, we ran three independent MD simulations up to 1 μs. The impact of the activator binding was studied by different analysis, such as essential dynamics and evaluation of conformational entropies, among others [4]. We concluded that A-769662 acts as a molecular glue, making an effective connection between β- and α-subunits that pre-organizes the ATP-binding site, favouring the binding of ATP, and explaining the increase of the AMPK activity. These findings pave the way to explore the structural features that underline the different sensitivity of AMPK isoforms to A-769662, i.e., try to discern why A-769662 is only active in the α2β1γ1 isoform, while other compounds are active with isoform β2

Elucidating the activation mechanism of AMPK by direct pan-activator PF-739

Adenosine monophosphate-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 heterotrimeric complexes, which exhibit notable differences in the sensitivity to direct activators. To comprehend the molecular factors of the activation mechanism of AMPK, we have assessed the changes in the structural and dynamical properties of b1- and b2-containing AMPK complexes formed upon binding to the pan-activator PF-739. The analysis revealed the molecular basis of the PF-739-mediated activation of AMPK and enabled us to identify distinctive features that may justify the slightly higher affinity towards the b1-isoform, such as the b1-Asn111 to b2-Asp111 substitution, which seems to be critical for modulating the dynamical sensitivity of b1- and b2 isoforms. The results are valuable in the design of selective activators to improve the tissue specificity of therapeutic treatment