@article{MTMT:32916822, title = {Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design}, url = {https://m2.mtmt.hu/api/publication/32916822}, author = {Bálint, Mónika Enikő and Zsidó, Balázs Zoltán and van der Spoel, David and Hetényi, Csaba}, doi = {10.3390/ijms23137313}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {32916822}, issn = {1661-6596}, abstract = {The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {van der Spoel, David/0000-0002-7659-8526} } @article{MTMT:32911710, title = {Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4}, url = {https://m2.mtmt.hu/api/publication/32911710}, author = {Börzsei, Rita and Zsidó, Balázs Zoltán and Bálint, Mónika Enikő and Helyes, Zsuzsanna and Pintér, Erika and Hetényi, Csaba}, doi = {10.3390/ijms23136878}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {32911710}, issn = {1661-6596}, abstract = {Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin-SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Pintér, Erika/0000-0001-9898-632X; Hetényi, Csaba/0000-0002-8013-971X} } @CONFERENCE{MTMT:32039844, title = {A somatostatin 4-es receptor és az endogén ligandum-komplex szerkezetének előállítása}, url = {https://m2.mtmt.hu/api/publication/32039844}, author = {Börzsei, Rita and Bálint, Mónika Enikő and Helyes, Zsuzsanna and Pintér, Erika and Hetényi, Csaba}, booktitle = {MABIT Bioinformatika 2020 online előadások}, unique-id = {32039844}, year = {2020}, pages = {10-10}, orcid-numbers = {Pintér, Erika/0000-0001-9898-632X} } @article{MTMT:31396188, title = {Small molecule somatostatin receptor subtype 4 (sst4) agonists are novel anti-inflammatory and analgesic drug candidates}, url = {https://m2.mtmt.hu/api/publication/31396188}, author = {Szőke, Éva and Bálint, Mónika Enikő and Hetényi, Csaba and Markovics, Adrienn and Elekes, Krisztián and Pozsgai, Gábor and Szűts, Tamás and Kéri, György and Őrfi, László and Sándor, Zoltán and Szolcsányi, János and Pintér, Erika and Helyes, Zsuzsanna}, doi = {10.1016/j.neuropharm.2020.108198}, journal-iso = {NEUROPHARMACOLOGY}, journal = {NEUROPHARMACOLOGY}, volume = {178}, unique-id = {31396188}, issn = {0028-3908}, abstract = {We provided strong proof of concept evidence that somatostatin mediates potent analgesic and anti-inflammatory actions via its receptor subtype 4 (sst4) located both at the periphery and the central nervous system. Therefore, sst4 agonists are promising novel drug candidates for neuropathic pain and neurogenic inflammation, but rational drug design was not possible due to the lack of knowledge about its 3-dimensional structure. We modeled the sst4 receptor structure, described its agonist binding properties, and characterized the binding of our novel small molecule sst4 agonists (4-phenetylamino-7H-pyrrolo[2,3-d]pyrimidine derivatives) using an in silico platform. In addition to the in silico binding data, somatostatin displacement by Compound 1 was demonstrated in the competitive binding assay on sst4-expressing cells. In vivo effects were investigated in rat models of neurogenic inflammation and chronic traumatic neuropathic pain. We defined high- and low-affinity binding pockets of sst4 for our ligands, binding of the highest affinity compounds were similar to that of the reference ligand J-2156. We showed potent G-protein activation with the highest potency of 10 nM EC50 value and highest efficacy of 342%. Oral administration of 100 μg/kg of 5 compounds significantly inhibited acute neurogenic plasma protein extravasation in the paw skin by 40-60%, one candidate abolished and 3 others diminished sciatic nerve-ligation induced neuropathic hyperalgesia by 28-62%. The in silico predictions on sst4-ligands were tested in biological systems. Low oral dose of our novel agonists inhibit neurogenic inflammation and neuropathic pain, which opens promising drug developmental perspectives for these unmet medical need conditions.}, keywords = {Inflammation; SOMATOSTATIN; Neuropathic pain; somatostatin receptor subtype 4; Analgesic drug; Anti-inflammatory drug}, year = {2020}, eissn = {1873-7064}, orcid-numbers = {Őrfi, László/0000-0001-6149-2385; Pintér, Erika/0000-0001-9898-632X} } @article{MTMT:31315404, title = {Ndr/Lats Kinases Bind Specific Mob-Family Coactivators through a Conserved and Modular Interface}, url = {https://m2.mtmt.hu/api/publication/31315404}, author = {Parker, B.W. and Gogl, G. and Bálint, Mónika Enikő and Hetényi, Csaba and Reményi, Attila and Weiss, E.L.}, doi = {10.1021/acs.biochem.9b01096}, journal-iso = {BIOCHEMISTRY-US}, journal = {BIOCHEMISTRY}, volume = {59}, unique-id = {31315404}, issn = {0006-2960}, year = {2020}, eissn = {1520-4995}, pages = {1688-1700} } @article{MTMT:31154020, title = {Systematic Exploration of Binding Modes of Ligands on Drug Targets}, url = {https://m2.mtmt.hu/api/publication/31154020}, author = {Hetényi, Csaba and Bálint, Mónika Enikő}, doi = {10.1007/978-1-0716-0270-6_8}, journal-iso = {METHODS MOL BIOL}, journal = {METHODS IN MOLECULAR BIOLOGY}, volume = {2112}, unique-id = {31154020}, issn = {1064-3745}, abstract = {Exploration of binding sites of ligands (drug candidates) on macromolecular targets is a central question of molecular design. Although there are experimental and theoretical methods available for the determination of atomic resolution structure of drug-target complexes, they are often limited to identify only the primary binding mode (site and conformation). Systematic exploration of multiple (allosteric or prerequisite) binding modes is a challenge for present methods. The Wrapper module of our new method, Wrap 'n' Shake, answers this challenge by a fast, computational blind docking approach. Beyond the primary (orthosteric) binding mode, Wrapper systematically produces all possible binding modes of a drug scanning the entire surface of the target. In several fast blind docking cycles, the entire surface of the target molecule is systematically wrapped in a monolayer of N ligand copies. The resulted target-ligandN complex structure can be used as it is, or important ligand binding modes can be further distinguished in molecular dynamics shakers. Wrapper has been tested on important protein targets of drug design projects on cellular signaling and cancer. Here, we provide a practical description of the application of Wrapper.}, keywords = {ANTAGONIST; INHIBITOR; MECHANISM; PEPTIDE; RECEPTOR; ENZYME; AGONIST; Interaction; POCKET; Action}, year = {2020}, eissn = {1940-6029}, pages = {107-121} } @misc{MTMT:31349705, title = {Calculation of complex structures of somatostatin receptors}, url = {https://m2.mtmt.hu/api/publication/31349705}, author = {Börzsei, Rita and Bálint, Mónika Enikő and Helyes, Zsuzsanna and Pintér, Erika and Hetényi, Csaba}, unique-id = {31349705}, abstract = {In the last decade, complex mechanisms of pain and the relationships between the sensory nerves, immune system, and vascular system have been thoroughly investigated. However, neuropathic pain due to traumatic, metabolic or toxic injury of the nerves still affects large patient population and there is no effective therapy for these people. The varied classic non-steroidal anti-inflammatory drugs (NSAIDs) are inefficient for neurogenic pain and opioids have an effect only in high doses. Adjuvant analgesics that are commonly used for epilepsy and depression might be effective in certain patients, but due to their severe side-effects, the long-term application is not possible [1]. According to the classic theory of nerve regulation, sensory nerves like capsaicin sensitive neurons, mediate different sensations to the central nervous system from the area of the skin, joints and other internal organs (classic afferent function). Besides their classic sensory/nociceptive functions neuropeptides release from the nerve endings causing vasodilatation, plasma protein extravasation and activation of inflammatory cells on the innervation area, and therefore, they evolve neurogenic inflammation (local efferent function). Furthermore, somatostatin (SST) also known as somatotropin release inhibitory factor gets into the systemic circulation and relieves the pain and neurogenic inflammation in other part of the body (systemic efferent function) [2]. SST effects are mediated via five somatostatin receptor (SSTR) subtypes which comprise two classes on basis of their phylogeny, structural homologies and pharmacological properties. Receptors with high affinity for octreotide, a synthetic SST analogue, were classified in the first class (SSTR2, SSTR3 and SSTR5), whereas the other class includes SSTR1 and SSTR4, displaying low or negligible affinity for the analogue [3]. Our group discovered that among the five inhibitory SST receptors SSTR4 mediates potent analgesic and anti-inflammatory effects without hormone secretion inhibition, therefore, it is a promising novel target for drug development [4]. All five receptors belong to the rhodopsin-like receptor family of G-protein coupled receptors (GPCRs) and possess seven transmembrane domains that provide the characteristic structure of GPCRs. Unfortunately, crystal structures have not been determined experimentally for any SSTR subtypes. However, common structural features, and conserved sequence in transmembrane regions have been identified. SST is an endogenous cyclic neuropeptide and widely expressed in the body, it occurs in the peripheral, as well as the central nervous system and plays an important role in regulation of the endocrine system, neurotransmission and cell proliferation. It occurs as a tetradecapeptide (SST-14) or an N-terminally extended form (SST-28). Both peptides contain disulphide bridge between cysteines at positions 3 and 14 which stabilizes the structure. Structure-activity relationship studies showed that in the pharmacophore region of SST included the Phe7-Trp8-Lys9-Thr10 tetrapeptide, Trp8 and Lys9 were essential for binding to all SSTR subtypes, whereas Phe6 is specifically important for SSTR4 activation [5,6]. The therapeutic application of native SST is limited due to its diverse biological effects and rapid degradation (<3 min half-life in the circulation), consequently there is a great need to identify metabolically stable, highly potent and receptor selective SST analogues as potential analgesic drug candidates. Despite the development of numerous SST analogues and recent release of new, potent molecules [7, 8, 9], the molecular structure of SSTRs and the exact binding site or modes of the ligands have not been determined experimentally. However, such information could be essential for the design of potent, receptor-selective drugs. The aim of our research group is the modelling of the structure of SSTRs, identification of the binding sites of the new ligands and the examination of binding mechanisms using target-ligand complexes. Due to the size of the receptors and the complexes, molecular mechanics methodologies are involved in our investigations. Well-established techniques of homology modelling [10, 11] and docking [12, 13] were applied. To answer the challenge of blind docking prediction of the binding mode of SST, our recent techniques Wrap ’n’ Shake [14] and fragment blind docking [15] were also adopted for the work. Preliminary findings of our research will be presented in the above-detailed physiological context of SSTRs. Acknowledgments This work was supported by the Hungarian National Research, Development and Innovation Office (K123836, K112807) and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. C.H. is thankful to the Új Nemzeti Kiválósági Program of the Hungarian Ministry for Innovation and Technology. We acknowledge the grant of computer time from CSCS Swiss National Supercomputing Centre, and the Governmental Information Technology Development Agency, Hungary. The University of Pécs is acknowledged for a support by the 17886-4/23018/FEKUTSTRAT excellence grant. C.H.’s work was supported by a grant co-financed by Hungary and the European Union (EFOP-3.6.2-16-2017-00008).}, year = {2019}, orcid-numbers = {Pintér, Erika/0000-0001-9898-632X} } @article{MTMT:30792970, title = {A Fragmenting Protocol with Explicit Hydration for Calculation of Binding Enthalpies of Target-Ligand Complexes at a Quantum Mechanical Level}, url = {https://m2.mtmt.hu/api/publication/30792970}, author = {Horváth, István and Jeszenői, Norbert and Bálint, Mónika Enikő and Paragi, Gábor and Hetényi, Csaba}, doi = {10.3390/ijms20184384}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {20}, unique-id = {30792970}, issn = {1661-6596}, abstract = {Optimization of the enthalpy component of binding thermodynamics of drug candidates is a successful pathway of rational molecular design. However, the large size and missing hydration structure of target-ligand complexes often hinder such optimizations with quantum mechanical (QM) methods. At the same time, QM calculations are often necessitated for proper handling of electronic effects. To overcome the above problems, and help the QM design of new drugs, a protocol is introduced for atomic level determination of hydration structure and extraction of structures of target-ligand complex interfaces. The protocol is a combination of a previously published program MobyWat, an engine for assigning explicit water positions, and Fragmenter, a new tool for optimal fragmentation of protein targets. The protocol fostered a series of fast calculations of ligand binding enthalpies at the semi-empirical QM level. Ligands of diverse chemistry ranging from small aromatic compounds up to a large peptide helix of a molecular weight of 3000 targeting a leukemia protein were selected for systematic investigations. Comparison of various combinations of implicit and explicit water models demonstrated that the presence of accurately predicted explicit water molecules in the complex interface considerably improved the agreement with experimental results. A single scaling factor was derived for conversion of QM reaction heats into binding enthalpy values. The factor links molecular structure with binding thermodynamics via QM calculations. The new protocol and scaling factor will help automated optimization of binding enthalpy in future molecular design projects.}, keywords = {BINDING; PEPTIDE; AFFINITY; DESIGN; WATER; Optimization; structure; Correlation; Interaction}, year = {2019}, eissn = {1422-0067}, orcid-numbers = {Jeszenői, Norbert/0000-0002-6472-5807; Paragi, Gábor/0000-0001-5408-1748} } @CONFERENCE{MTMT:30678397, title = {Interactions of zearalenone and its reduced metabolites with serum albumins and cyclodextrins}, url = {https://m2.mtmt.hu/api/publication/30678397}, author = {Faisal, Anna Zelma and Virág, Vörös and Jakabfi-Csepregi, Rita and Kőszegi, Tamás and Lemli, Beáta and Kunsági-Máté, Sándor and Bálint, Mónika Enikő and Hetényi, Csaba and Lajos, Szente and Poór, Miklós}, booktitle = {5th International Cholnoky Symposium}, unique-id = {30678397}, year = {2019}, pages = {9-9}, orcid-numbers = {Lemli, Beáta/0000-0001-8903-1337} } @mastersthesis{MTMT:30545382, title = {Systematic exploration of multiple drug binding sites}, url = {https://m2.mtmt.hu/api/publication/30545382}, author = {Bálint, Mónika Enikő}, doi = {10.15476/ELTE.2018.091}, unique-id = {30545382}, year = {2019} }