title: The in silico identification of small molecules for protein-protein interaction inhibition in AKAP-Lbc-RhoA signaling complex.
abstract: The rational design of small molecules that mimic key residues at the interface of interacting proteins can be a successful approach to target certain biological signaling cascades causing pathophysiological outcome. The A-Kinase Anchoring Protein, i.e. AKAP-Lbc, catalyses nucleotide exchange on RhoA and is involved in cardiac repolarization. The oncogenic AKAP-Lbc induces the RhoA GTPase hyperactivity and aberrantly amplifies the signaling pathway leading to hypertrophic cardiomyocytes. We took advantage of the AKAP-Lbc-RhoA complex crystal structure to design in silico small molecules predicted to inhibit the associated pathological signaling cascade. We adopted the strategies of pharmacophore building, virtual screening and molecular docking to identify the small molecules capable to target AKAP-Lbc and RhoA interactions. The pharmacophore model based virtual screening unveils two lead compounds from the TIMBAL database of small molecules modulating the targeted protein-protein interactions. The molecular docking analysis revealed the lead compounds' potentialities to establish the essential chemical interactions with the key interactive residues of the complex. These features provided a road map for designing additional potent chemical derivatives and fragments of the original lead compounds to perturb the AKAP-Lbc and RhoA interactions. Experimental validations may elucidate the therapeutic potential of these lead chemical scaffolds to deal with aberrant AKAP-Lbc signaling based cardiac hypertrophy.
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan; Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: asif@awkum.edu.pk.
authors.forename: Asifullah
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
authors.forename: Mehwish
authors.initials: M
authors.lastname: Munir
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
authors.forename: Sara
authors.initials: S
authors.lastname: Aiman
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.affiliation: Ripha Institute of Pharmaceutical Sciences, Ripha International University Islamabad, Pakistan.
authors.forename: Arif-Ullah
authors.initials: AU
authors.lastname: Khan
mesh_terms: D054758:A Kinase Anchor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D004791:Enzyme Inhibitors; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: AKAP-Lbc; Drug designing; Molecular docking; Protein-protein interaction inhibitors