Androgen receptor is an important target for the treatment of prostate cancer, and mutations in the androgen receptor have an important impact on the resistance of existing drugs. In this work, we performed molecular dynamics simulations of the existing marketed antiandrogens flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide and its main metabolite ORM15341 in complex with the wild-type and F876L mutant androgen receptor. We calculated the residue-specific binding free energy contribution of the wild-type and mutant androgen receptors with the AS-IE method, and analyzed the hot-spot residues and the binding free energy contributions of specific residues before and after the mutation. In addition, we analyzed the total binding obtained by adding residue binding energy contributions and compared the results with experimental values. The obtained residue-specific binding information should be very helpful in understanding the mechanism of drug resistance with respect to specific mutations and in the design of new generation drugs against possible new mutations.
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